Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Postprandial lipaemia, metabolic syndrome and LDL particle size in urbanised South African blacks with and without coronary artery disease.

BACKGROUND: Postprandial lipaemia, characterised by a rise in triglycerides (TG) after eating, is associated with coronary artery disease (CAD) and metabolic syndrome (MetS). Small, dense, low-density lipoprotein (LDL) particles are implicated in atherogenesis. Little is known about postprandial lipaemia or small, dense LDL particles in urbanised black South Africans. AIMS: Assess postprandial lipaemia in black CAD patients with and without MetS and measure their fasting and postprandial lipid profiles and LDL particles. METHODS: Anthropometric data, biochemical variables and LDL particles were measured in 40 patients and 20 control subjects. Twenty three patients met International Diabetes Federation criteria for MetS and were subdivided according to fasting TG concentration either < or > or = 1.7 mmol/l. Postprandial lipaemia was assessed by an oral fat tolerance test (OFTT) and area under the curve (AUC). RESULTS: CAD patients with and without MetS had similar fasting lipid profiles, postprandial responses during OFTT and AUCs. MetS patients with fasting TG > or = 1.7 mmol/l had greater postprandial responses (P < 0.001) and higher AUC (P < 0.0001) than patients with TG < 1.7 mmol/l. AUC was higher in all patients than controls (P < 0.03). The most significant correlation was between fasting TG and AUC (r = 0.8703; P < 0.0001). Small, dense LDL particles were present in 29 patients (72.5%) and 3 controls (15%) (p = 0.0001). CONCLUSION: Postprandial lipaemia was common in black CAD patients, including patients with MetS. Fasting TG concentration was the strongest determinant. Small, dense LDL particles were highly associated with CAD.

Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy.

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.

Relationship between plasma insulin and blood pressure in South African black women in Johannesburg.

OBJECTIVE: To examine the relationship between fasting plasma insulin and blood pressure (BP) in 40 urbanized normotensive South African black women aged 24-60 yr, and to assess the effects of body mass index (BMI) and fasting plasma glucose on BP. RESEARCH DESIGN AND METHODS: The women comprised equal numbers of young nonobese nondiabetic subjects, middle-aged nonobese nondiabetic subjects, middle-aged obese nondiabetic subjects, and middle-aged obese newly diagnosed non-insulin-dependent diabetic subjects. Systolic and diastolic BPs were recorded (in duplicate) after 15 min of recumbency, and fasting plasma glucose and insulin levels were determined thereafter. The data were analyzed by simple and multivariate regression. RESULTS: There was a wide distribution of individual physical and biochemical features. With simple correlations, systolic BP correlated significantly with age, BMI, and fasting glucose but not with insulin. Diastolic BP correlated significantly with all four variables (r = 0.37, P less than 0.05). When adjusted for age, BMI, and glucose, however, the significant correlation between diastolic BP and insulin diminished (r = -0.04). CONCLUSIONS: As in other nonwhite communities, plasma insulin does not appear to play a major role in regulating the BP of South African black women.

Insulin-receptor activity in nondiabetic and diabetic urbanized South African black women.

OBJECTIVE: To evaluate insulin receptor binding characteristics of urbanized South African black women with normal glucose tolerance and of patients with newly diagnosed untreated non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Four groups of 10 subjects each were selected by the following criteria: group A, young (20-39 yr) nonobese (body mass index [BMI] 19.0-24.9 kg/m2) nondiabetic women; group B, middle-aged (40-60 yr) nonobese nondiabetic women; group C, middle-aged obese (BMI greater than 30.0 kg/m2) nondiabetic women; and group D, middle-aged obese newly diagnosed but untreated female patients with NIDDM. Insulin binding to monocyte receptors was determined by radioreceptor assay. Fasting plasma samples were analyzed for glucose, insulin, C-peptide, and nonesterified fatty acids. RESULTS: In the four groups studied, maximum specific binding and receptor concentration were highest in group A, with a progressive and significant decrease in values through groups B and C to group D. Significant inverse correlations were obtained between maximum specific binding, 50% inhibition dose, and total receptor concentration on the one hand and glucose, insulin, and NEFA on the other. CONCLUSIONS: Our study of urban South African black women showed decreasing insulin-receptor activity with obesity and glucose intolerance. In patients with NIDDM, hyperglycemia and beta-cell dysfunction were associated with a reduction in receptor concentration. In this regard, our findings in South African blacks are consistent with results of similar studies of NIDDM in other communities.

Effect of moderate dietary protein restriction on the progression of overt diabetic nephropathy: a 6-mo prospective study.

To assess whether moderate dietary protein restriction can delay the progression of overt diabetic nephropathy, 22 subjects with insulin-dependent diabetes mellitus were randomly assigned to an unrestricted protein diet (> 1.6 g.kg body wt-1.d-1) or a moderately protein-restricted diet (0.8 g.kg body wt-1.d-1) and followed prospectively for six mo. Direct isotope methods were used to assess renal function. Protein intake was assessed by measurement of urinary urea nitrogen. The two groups were well-matched for age, sex, duration of diabetes, glycemic control, blood pressure, and degree of renal insufficiency. Patients consuming the unrestricted protein diet (n = 11) showed a progressive decline in glomerular filtration rate of 1.3 mL.min-1.mo-1 with no change in proteinuria. Patients consuming the moderately protein-restricted diet showed a marked decrease in the degree of proteinuria (2.15-1.13 g/d, P = 0.036) and a stabilization of glomerular filtration rate. This occurred independently of changes in blood pressure or glycemic control. Moderate dietary protein restriction can ameliorate progression of overt diabetic nephropathy.

Nocturnal events related to "morning dipping" in bronchial asthma.

The mechanism of early morning bronchospasm in asthma was investigated by analyzing circadian variations in the plasma levels of cortisol, ACTH, epinephrine, and norepinephrine, as well as in the serum neutrophil chemotactic activity and heart rate in asthmatic patients with (n = 6) and without (n = 7) "morning dipping" and normal subjects. Findings suggested that an exaggerated nocturnal nadir in plasma cortisol levels may precipitate "morning dipping" in some patients with asthma.

Hypoglycemia in hepatocellular carcinoma: failure of short-term growth hormone administration to reduce enhanced glucose requirements.

The mechanism of tumor-associated hypoglycemia was investigated in 10 (six hypoglycemic and four normoglycemic) southern African blacks with hepatocellular carcinoma. The mean basal blood glucose concentration was significantly lower (2.4 +/- 0.1 v 3.6 +/- 0.2 mmol/L; P less than .01) and steady-state exogenous glucose requirements were increased fourfold (3.6 +/- 0.6 v 0.97 +/- 0.2 mg/kg/min; P less than .01) in the hypoglycemic compared with the normoglycemic patients. Plasma insulin and C-peptide levels were suppressed to the lower limit of sensitivity of each of the assays in both groups of patients. The concentrations of insulin-like growth factors (IGF) I and II were lower (19 +/- 1.6 v 25 +/- 4.6 insulin-like growth factors (IGF) I and II were lower (19 +/- 1.6 v 25 +/- 4.6 ng/L) and higher (230 +/- 42 v 173 +/- 40 ng/L), respectively, in the hypoglycemic patients, although the differences were not statistically significant. Of the counterregulatory hormones measured, only the growth hormone (GH) concentration was significantly lower in the hypoglycemic patients (0.9 +/- 0.2 v 18.6 +/- 5.6 micrograms/L; P less than .01). Correction of the plasma GH level into the high-normal physiological range in two hypoglycemic patients failed to reduce steady-state exogenous glucose requirements. However, the glucose requirements were reduced from 2.6 to 1.1 mg/kg/min in the same two patients when "acromegalic" plasma concentrations of GH were achieved. We conclude that steady-state glucose requirements are increased in black patients with hypoglycemia complicating hepatocellular carcinoma, and that short-term correction of the associated hyposomatotropism fails to reduce the enhanced requirements.

Insulin-mediated glucose disposal in black south Africans with essential hypertension.

We used the hyperinsulinaemic euglycaemic clamp method to assess insulin-mediated glucose disposal in ten black South African patients with newly-diagnosed essential hypertension, compared to ten normotensive controls. The patients were all nonobese with normal glucose tolerance. Comparisons were made before and 12 weeks after treatment with a long-acting ACE inhibitor. The mean glucose disposal (M) and disposal expressed as glucose sensitivity index (M/I) were significantly reduced in the hypertensives vs. controls (M: 6.8 +/- 0.9 vs. 9.7 +/- 0.8 mg/kg/min; MI: 7.1 +/- 1.0 vs. 12.5 +/- 1.7 mg/kg/min/mU/l x 100) (p = 0.03 and 0.01, respectively). Following therapy, M/I increased in the patients to values not significantly different to those of the controls. Insulin resistance is an independent feature of essential hypertension in black South African patients, and is partially corrected by treatment with a long-acting ACE inhibitor.

Prior long term glycaemic control and insulin therapy in insulin-dependent diabetic adolescents with microalbuminuria.

Adolescence seems to be a period of increased risk for the initiation of diabetic renal disease in insulin-dependent diabetic children. Poor glycaemic control is a risk factor for diabetic nephropathy. We have therefore evaluated prior long-term glycaemic control in 23 diabetic adolescents with microalbuminuria (albumin excretion rate (AER) 20-200 micrograms/min, median 39.0 micrograms/min) and in 23 matched diabetic controls with AER less than 20 micrograms/min (median 9.3 micrograms/min). Glycaemic control was assessed by mean HbA1 and clinic blood glucose levels over a period ranging from 12 to 84 months (median 48 months). Mean HbA1 was 13.6 +/- 2.0% in the microalbuminuric subjects, compared to 11.5 +/- 2.2% in the controls (P less than 0.002); mean blood glucose levels were 13.5 +/- 3.0 and 11.4 +/- 3.0 mmol/l, respectively (P less than 0.02). There appeared to be a 'threshold effect' (mean HbA1 greater than 12.0%), above which the development of microalbuminuria was more likely. More patients with microalbuminuria than controls had been treated with a single rather than twice-daily insulin injections (P less than 0.001), and glycaemic control was significantly worse in patients treated with one injection. We conclude that poor long term glycaemic control is a risk factor for microalbuminuria, and that improving control during childhood is likely to reduce the prevalence of later microalbuminuria. Two insulin injections, of combined intermediate and short-acting preparations, are more likely to provide better control than a single daily insulin dose.

The relationship between the development and progression of microalbuminuria and arterial blood pressure in type 1 (insulin-dependent) diabetes mellitus.

OBJECTIVE: to investigate the association between urinary albumin excretion and arterial blood pressure in type 1 (insulin-dependent) diabetes. RESEARCH DESIGN AND METHODS: urinary albumin excretion and blood pressures were followed prospectively for a mean period of 26 months (range 18-29 months) in 46 young type 1 (insulin-dependent) diabetic subjects without overt nephropathy. Supine blood pressures (BP) were measured by a single observer using a random zero sphygmomanometer. Albumin excretion was assessed at baseline by a timed clinic excretion rate (AER; microalbuminuria = AER greater than 33 micrograms/min), and at follow-up in at least two urine specimens by the albumin/creatinine (A/Cr) ratio (micro-albuminuria = A/Cr greater than 3.7 mg/mmol). RESULTS: 39 subjects initially had normal AERs. Seven had developed microalbuminuria at follow-up: their mean BP rose from 114 +/- 13/62 +/- 13 to 119 +/- 7/77 +/- 5 mmHg (for diastolic BP, P less than 0.05), while there was no change in the mean BP in the remaining 32 patients. A rise in diastolic BP of greater than 10 mmHg occurred in five of the seven subjects who developed microalbuminuria, and in only seven of 32 who did not (P = 0.02). In the seven patients in whom microalbuminuria persisted (n = 3) or progressed to overt proteinuria (n = 4), BP increased from 123 +/- 12/70 +/- 14 to 139 +/- 12/88 +/- 10 mmHg (P less than 0.02 for both). CONCLUSIONS: this study has shown that BP is normal before the onset of microalbuminuria, and that a rise in diastolic BP accompanies the development or progression of microalbuminuria. The rate of rise in BP may be more important than the absolute level in defining 'hypertension' in young diabetic patients with microalbuminuria.

The prevalence of micro-albuminuria and glomerular hyperfiltration in young patients with IDDM.

We have assessed the prevalence of two risk factors for diabetic nephropathy, i.e., micro-albuminuria and a raised glomerular filtration rate (GFR), in 127 insulin-dependent diabetic patients aged 13-36 years. Micro-albuminuria (albumin excretion rate (AER) 20-200 micrograms/min) was found in 46 subjects (36%) and GFR was elevated (greater than 135 ml/min/1.73 m2) in 43 (34%). The prevalence of supranormal GFR declined and that of micro-albuminuria rose progressively with the increasing duration of diabetes. While age and sex distribution were similar in subjects with and without raised AER, duration of diabetes was significantly longer, blood pressure (BP) was significantly greater and age of onset was lower in the micro-albuminuria group. Blood pressure was significantly elevated only in the patients with AER of 70-200 micrograms/min; there was a linear trend for BP to rise as AER increased. Stepwise logistic regression analysis indicated that duration of diabetes (P less than 0.0001), age of onset of diabetes (P less than 0.005) and current glycaemic control (HbA1) (P less than 0.01) were risk factors for micro-albuminuria. The association with a rising blood pressure appears to be secondary to the renal involvement. In this cross-sectional study an association of micro-albuminuria with a raised GFR could not be demonstrated.

Determination of cholesterol and triglycerides in blood: a comparison between wet chemistry methods and a dry chemistry analyser.

Total cholesterol and triglyceride concentrations in 127 samples of capillary and venous blood were measured with the portable Reflotron 'dry chemistry' reflectometer and compared with serum levels measured in the laboratory using wet chemistry methods. Results were grouped into low, middle and high ranges. Levels measured with the Reflotron correlated closely with those measured by wet chemistry methods. Reflotron values for both lipid fractions were, however, consistently higher than wet chemistry levels but the differences were small except at high levels. It is concluded that the Reflotron is a satisfactory instrument for providing clinically useful measurements of cholesterol and triglyceride nearer to the patient.

Metabolic syndrome, undiagnosed diabetes mellitus and insulin resistance are highly prevalent in urbanised South African blacks with coronary artery disease.

BACKGROUND: The prevalence of coronary artery disease (CAD) is low in South African blacks, despite increasing westernisation and the accompanying rise in risk factors that are common to CAD and the metabolic syndrome (MS). AIM: To assess the prevalence of the MS and abnormal glucose regulation in black patients with established CAD, who had no previously known diabetes mellitus (DM). METHODS: In 40 patients, anthropometric and biochemical variables were measured by standard methods. MS risk factors were analysed according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Glucose regulation was assessed by the oral glucose tolerance test, and insulin resistance was evaluated using the hyperinsulinaemic euglycaemic clamp technique (M-value). RESULTS: MS was present in 24 patients (60%) and absent in 16 patients (40%). Abdominal obesity, measured as increased waist circumference (WC), was the risk factor that differentiated the two groups and, together with hypertension and elevated glucose, formed the most frequent risk-factor combination. No significant differences were found in the proportions of males or females above and below the various cut-off points for gender-associated risk factors (WC and HDL cholesterol). There was a significant correlation between WC and M-value (r = -0.3595; p = 0.02). Half the patients had abnormal glucose regulation, comprising impaired glucose tolerance (IGT) in 30% and DM in 20% of the patient cohort. CONCLUSIONS: MS was highly prevalent in our black patients with CAD. Increased WC was the most important risk factor and, together with hypertension and elevated glucose, formed the most frequent risk-factor combination. Abdominal obesity was significantly related to insulin resistance. Previously undiagnosed impaired glucose tolerance (IGT) and DM were common abnormalities.

Adrenocortical function in hospitalised patients with active pulmonary tuberculosis receiving a rifampicin-based regimen -- a pilot study.

OBJECTIVE: To assess whether adrenocortical function was compromised in patients with active tuberculosis (TB) during the first 5 days of therapy with either a rifampicin-based or ciprofloxacin-based regimen. DESIGN: Patients were randomised into two groups of 10 each. Adrenocortical function was compared in both groups by the measurement of biochemical indices, electrolytes, osmolality and pituitary-adrenocortical hormones. Adrenal reserve was assessed by intravenous 250 mug adrenocorticotropin hormone (ACTH) stimulation tests. SETTING: Department of Medicine, Johannesburg Hospital. SUBJECTS: Twenty hospitalised patients who were diagnosed with TB. OUTCOME MEASURES: Respiratory rate, pulse rate and blood pressure were recorded, and urinary sodium and osmolality were measured. Serum ACTH, cortisol, dehydroepiandrosterone- sulphate (DHEA-S) and aldosterone were assayed. RESULTS: None of the patients demonstrated biochemical evidence of overt adrenal insufficiency. There were no significant differences between the two groups before or during therapy for any biochemical indices, electrolytes, hormones or calculated osmolality. Mean basal cortisol concentrations were substantially elevated and DHEA-S levels were consistently subnormal, resulting in a high cortisol/ DHEA-S ratio. In the ciprofloxacin group, cortisol responses to ACTH stimulation on day 1 were not significantly lower than on day 5. In the rifampicin group, cortisol concentrations decreased at each time point on day 5 compared with day 1 (p = 0.001). However, a significantly higher mean incremental rise from the basal cortisol concentration was measured on day 5 at 60 minutes (p = 0.04). In the entire cohort of 20 patients, 40% demonstrated an incremental cortisol rise of < 250 nmol/l after ACTH stimulation on day 1. CONCLUSIONS: Rifampicin did not additionally impair adrenocortical function during the initial period of therapy. The high cortisol/DHEA-S ratio might be of clinical relevance.

Performance of the CardioChek PA and Cholestech LDX point-of-care analysers compared to clinical diagnostic laboratory methods for the measurement of lipids.

Point-of-care (POC) blood testing is intended to provide results more rapidly than can be obtained from a central laboratory. Precision and accuracy of the CardioChek PA and Cholestech LDX analysers were compared to clinical diagnostic laboratory methods. In 100 patients, total cholesterol (TC), triglycerides (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels were measured by both analysers and compared to those analysed by the National Health Laboratory Service (NHLS) laboratory. Data were evaluated for conformance with National Cholesterol Education Program (NCEP) guidelines. Results were grouped into low, middle and high ranges and were similar to those obtained by the NHLS, except in the high range where TC and LDL-C levels were under-read by both analysers. All analytes measured by both analysers correlated significantly with NHLS (p < 0.0001). With the exception of LDL-C, both analysers showed reasonable compliance with NCEP goals for coefficients of variation and bias measurements. Both analysers met NCEP guidelines for all analytes at two clinical cut-off points. We concluded that, compared to NHLS methods, performance of the CardioChek PA and Cholestech LDX analysers is acceptable and that they offer healthcare professionals a rapid, POC method for the measurement of lipids.

Thyroid-associated ophthalmopathy in black South Africans with Graves' disease: relationship to serum antibodies reactive against eye muscle and orbital connective tissue autoantigens.

The prevalence of hyperthyroidism owing to Graves' disease is increasing among urban black South Africans. Thyroid-associated ophthalmopathy is often observed in this context, but its pathogenesis remains unclear. No close relationship has been noted between antiflavoprotein (Fp) antibodies or thyrotropin receptor antibodies and ocular involvement in black patients. We measured serum antibodies against eye muscle and orbital connective tissue antigens in black patients with Graves' disease, correlating them with eye signs. Of 11 patients with clinical ophthalmopathy, 2 (18%) had antibodies against collagen type XIII, 3 (27%) against flavine adenine dinucleotide (FAD), 1 (9%) against Fp, and 4 (35%) against G2s. Antibody prevalences in eight patients without clinical ophthalmopathy were 12.5% for collagen XIII, 12.5% for FAD, 25% for Fp and 0% for G2s. These differences were not statistically significant. None of the individual mean antibody levels were significantly different between the two subgroups of thyrotoxic patients. Serum antibody levels were negative in 10 black South African controls. In summary, eye muscle and orbital connective tissue antibodies were found in small proportions of patients with Graves' disease with no close relationship of any antibody to eye signs. Thus, a substantial proportion of black South Africans with overt clinical ophthalmopathy remains in whom currently availabe serologic tests are unhelpful for screening and laboratory confirmation.

Metabolic and hormonal responses to salbutamol in asthma. Evidence of beta-adrenergic overactivity?

The possibility that beta-adrenergic hyposensitivity may be involved in the pathogenesis of bronchial asthma remains a controversial issue. The hormonal, metabolic and cardiovascular responses to selective beta 2-adrenergic stimulation with salbutamol were compared in 11 asthmatic and 11 non-asthmatic subjects. There was no consistent difference between the two groups in the plasma free fatty acid, glucose and potassium responses, or in the cardiovascular variables studied, but the asthmatic patients demonstrated a marked dose-dependent hyperinsulinaemic response to salbutamol. Although this phenomenon cannot be accounted for with certainty, it may be a manifestation of pancreatic beta-adrenergic overactivity which would not be in keeping with the concept of generalised hyposensitivity of beta-adrenergic mechanisms in asthma. The present results provide a clear demonstration of the difficulties involved in attempts to relate extrapulmonary autonomic phenomena to the pathogenesis of bronchial asthma.

Thyrotropin receptor antibodies in black South African patients with Graves' disease and their response to medical therapy.

Graves' disease is increasing in incidence amongst urban black South Africans. The pathogenic role of thyrotropin receptor antibodies (TRAb), crucial in other populations, has not been formally evaluated in African communities. We therefore prospectively investigated the prevalence of TRAb in 30 consecutive urban black South African patients with classical Graves' disease at the onset of their illness. This was compared with the frequency of thyroid microsomal and thyroglobulin antibodies in the same patients. Ten patients with euthyroid goitres unrelated to Graves' disease and 10 healthy controls were also studied. Twenty of the hyperthyroid patients were retested 4-6 months after starting carbimazole therapy and ten of them again after 1 year. Initially 83% of patients were positive for TRAb as against 54% for thyroid microsomal and 1 7% for thyroglobulin antibodies. After 4-6 months of treatment, 65% of patients still had elevated (>15% inhibition of binding) TRAb titres, while at 1 year this had dropped to 40% (4 out of 10 patients). All positive patients had relapsed biochemically, while TRAb negative patients were all in remission. We conclude that TRAb are a sensitive and specific marker of Graves' disease in black South Africans and closely parallels the response to medical therapy at 1 year. However, their predictive value for delayed relapse requires the study of a larger cohort of patients over a longer time-frame.