Familial hypercholesterolaemia in South Africans: tracking findings and developments over time - with reference to : prevalence of hypercholesterolaemia in young Afrikaners with myocardial infarction. Ischaemic heart disease risk factors.

This review discusses the 1987 article by Wyndham, Seftel, Pilcher and Baker on familial hypercholesterolaemia (FH) and myocardial infarction (MI) in young Afrikaners, in terms of the significance at the time of publication, as well as the relevance of their findings versus current observations on hypercholesterolaemia in South Africa. Risk factors for coronary heart disease (CHD) were investigated in this study, with specific reference to familial hypercholesterolaemia. The significance of Wyndham's article is evaluated with regard to the contributions on hypercholesterolaemia by other South African researchers that preceded this publication. The clinical diagnostic criteria that were applied to identify possible FH at the time of publication are compared with currently employed criteria and guidelines. This review also acknowledges and honours other clinicians and researchers who, like Wyndham et al., have made significant contributions to the diagnosis and treatment of FH in South Africans.

Biological variation of ischaemia-modified albumin in healthy subjects.

AIM: Ischaemia-modified albumin (IMA), as measured by the albumin-cobalt binding (ACB) test, has been cleared by the US Food and Drug administration as a biomarker to exclude the presence of myocardial ischaemia in patients. Although there are a number of published studies detailing the clinical utility of IMA, data on the biological variation of IMA are still lacking. In this study we determined the analytical and biological variance components of ischaemia modified albumin, and compared the distribution of IMA values in our patient population to those provided by the kit manufacturer. METHODS: IMA was determined once a week for five consecutive weeks on a cohort of healthy subjects using a colorimetric method, the A CB test on a Roche modular analyser. RESULTS: The analytical coefficient of variation (CV(A)) was 5%, and the within-subject (CV(I)) and between-subject (CV(G)) biological variations were 3 and 7%, respectively. Analysis of the repeated measures with gender and race (black and Caucasian) as between-subject factors, and weeks (1-5) as the within-subject factor showed that gender had no significant effect on circulating IMA concentrations (p = 0.3146), whereas race did have a significant effect (p = 0.0062). A significant (p = 0.0185) interaction was observed between gender and race. CONCLUSION: The ACB test could bring a new dimension to the care and management of patients with acute coronary syndrome. Further studies for normal population distributions by gender and ethnicity, and an optimum cut-off value appear to be required.

Simultaneous exposure to low concentrations of dichlorodiphenyltrichloroethane, deltamethrin, nonylphenol and phytoestrogens has negative effects on the reproductive parameters in male Spraque-Dawley rats.

Many reports suggest that male reproductive health has deteriorated over the last decades, possibly due to environmental contaminants that act as endocrine disruptors. This hypothesis was tested in Sprague-Dawley rats using a modified Organization for Economic Cooperation and Development 415 one-generation test. Group A received cottonseed oil as control, and Groups B, C and D received deltamethrin (DM); DM and dichlorodiphenyltrichloroethane (DDT); and DM, DDT, phytoestrogens and p-nonylphenol, respectively. Rats were exposed in utero and then received the substances for 10 weeks. The seminal vesicle mass (Group B; P = 0.046) and sperm count [Groups C (P = 0.013) and D (P = 0.003)] were lower and the anogenital distance [Group B (P = 0.047) C (P = 0.045) and D (P = 0.002)] shorter compared with the control group. The seminiferous tubule diameter [Groups B (P = <0.001), C (P = <0.001) and D (P = <0.001)] and epithelium thickness [Groups B (P = 0.030), C (P = <0.001) and D (P = <0.001)] were smaller compared with the control. The histology of the testes showed signs of apical sloughing and vacuolisation. Liver weights [Groups C (P = 0.013) and D (P = 0.005)] and liver enzymes [Group D (P = 0.013)] were also affected. These findings may indicate that simultaneous exposure to endocrine disrupting compounds contributes to the deterioration observed in male reproductive health.

Allelic variation in the promoter region of the LDL receptor gene: analysis of an African-specific variant in the FP2 cis-acting regulatory element.

DNA samples of 2303 individuals from nine different population groups were screened for variant -175g-->t in the promoter region of the low-density lipoprotein receptor (LDLR) gene. The -175g-->t variant detected at carrier frequencies of 3-10% in different African population groups was absent in the Caucasian and Asian (Chinese) individuals studied. In contrast to previous findings in Black South Africans where this polymorphism predominated in patients with familial hypercholesterolaemia (FH), it occurred at a significantly lower frequency in hypercholesterolaemics from the recently admixed Coloured population of South Africa compared with population-matched controls (P<0.0001). Haplotype and mutation analysis excluded the likelihood that this finding is due to association with a specific disease-related mutation in FH patients, although reversal of the positive association with FH observed in the Black population may, at least in part, be due to admixture linkage disequilibrium. Transient transfection studies in HepG2 cells demonstrated that the -175t allele is associated with a non-significant decrease ( approximately 7%) of LDLR transcription in the absence of sterols. The data presented in this study raise the possibility that the -175g-->t polymorphism may have subtle effects that become clinically important within certain genetic and/or environmental contexts.

Hepatitis B--a major threat to childhood survivors of leukaemia/lymphoma.

This prospective descriptive study was undertaken to determine: the proportion of paediatric oncology patients with prior exposure to hepatitis B at cancer diagnosis; the risk and risk factors for acquisition of hepatitis B infection during chemotherapy; and the development of a prevention policy. Sixty African children were included in this study. At the time of cancer diagnosis, 67.7 per cent had not been exposed to hepatitis B, and none had active infection. After follow-up (median of 20 months; range 4-81 months) 23.3 per cent had active hepatitis B infection, which was subclinical in the majority of cases. The diagnosis of leukaemia/lymphoma posed a major risk factor for the acquisition of active hepatitis B infection (chi-square 7.0; p-value = 0.008), probably due to intensive chemotherapy regimens and severity of immunosuppression. No association with gender, age, place of origin, or number of blood transfusions was found. Patients with leukaemia/lymphoma were at an increased risk for horizontal transmission of hepatitis B. A policy of active surveillance for infective carriers of hepatitis B infection and passive immunization of seronegative immunosuppressed patients must be implemented to limit the endemic infection in paediatric oncology units.

Hyperhomocyst(e)inemia, related vitamins and dementias.

Vitamin B12 and to a lesser extent folate deficiencies have been associated with dementias. Both these vitamins are determinants of plasma total homocysteine concentrations. In this review the frequency distributions of plasma vitamin B12, folate and homocysteine in South African males (# 51 yrs and > 51 yrs) illustrate the lower vitamin B12 levels in older subjects, and the shift toward elevated homocysteine concentrations in elderly people. Vitamin B12 deficiency appears to be associated with neuropsychiatric disorders, including dementias, but no causal relationship based on biochemical evidence has so far been established. Supplementation with vitamin B12 improves some neurological abnormalities and reverses only mild dementia of recent onset, but does not slow the progression of dementia. Elevated homocysteine levels appears to affect cognitive function, as measured by spatial copying skills and visual event-related potentials. Measurement of plasma homocysteine may help identify individuals with vitamin deficiencies and hyperhomocysteinemia. The relation between B-vitamins, homocysteine and dementia needs to explored further before vitamin supplementation is advocated to prevent or reverse neuropsychiatric disorders.

Effect of magnesium supplementation on the fractional intestinal absorption of 45CaCl2 in women with a low erythrocyte magnesium concentration.

The cosupplementation of magnesium with calcium has been suggested to be beneficial in the prevention of osteoporosis. We investigated the effect of magnesium supplementation on parameters of bone resorption and fractional 45Ca absorption. Twenty apparently healthy women with a mean age of 39.2 +/- 9.2 years and an erythrocyte magnesium concentration less than 1.97 mmol/L were recruited into a controlled magnesium supplementation trial. During weeks 1 to 4, they received a daily control preparation, potassium/sodium citrate malate (PSCM). During weeks 5 to 8, the subjects received magnesium citrate malate (MCM) equivalent to 250 mg magnesium per day. During the fourth and eighth weeks, blood was collected for measurement of the serum intact parathyroid hormone (PTH) concentration and serum and erythrocyte magnesium concentration. Urine was collected for measurement of calcium, magnesium, creatinine, and deoxypyridinoline excretion. On the final day of each treatment period, 5 microCi45CaCl2 was administered orally, and the isotope was traced in the blood and urine over 7 hours. Urinary calcium, 45Ca, and deoxypyridinoline excretion, as well as serum intact PTH levels, showed no statistically significant changes as a result of magnesium supplementation. However, urinary magnesium excretion increased by 31.1% (P < .005) while fractional 45Ca absorption decreased by 23.5% (P < .001) as a result of magnesium supplementation. It is concluded that magnesium supplementation does not result in changes in bone resorption, while the fractional intestinal absorption of 45Ca appears to decrease.

Ischemic heart disease in black South African stroke patients.

BACKGROUND AND PURPOSE: Stroke patients in western countries frequently have coronary artery disease (CAD). In black Africans, CAD has been reported as being rare in both stroke patients and the general population. In this study, an attempt has been made to determine the prevalence of CAD in a black South African stroke population. METHODS: The prevalence of CAD was determined by indicators identified through a series of 5 observational studies in black patients diagnosed with stroke. CAD indicators included (1) bedside diagnosis in 741 patients; (2) resting ECG in 555 consecutively admitted patients; (3) a combination of clinical examination, cardiac ultrasound, radionuclide scintigraphy, and multigated blood pool studies in 102 consecutively admitted patients; (4) thallium scintigraphy in 60 patients; and (5) necropsy in 23 patients. RESULTS: On bedside questioning, only 0.7% complained of previous angina. There was no history given of myocardial infarction (MI), but documentation of this was found in the clinical notes of 0.7% of the patients. In the resting ECG study, evidence of myocardial ischemia was present in 14.6% and MI in 2.1%. In the combined study, cardiac ischemia was documented on ECG in 12.7% of patients and evidence of previous MI in 5.8%. Cardiac scintigraphic studies revealed changes of myocardial ischemia in 31.7% and MI in 13.3% of the 60 patients studied. Four (17.4%) of 23 patients in the necropsy study had histological evidence of previous MI, and 50% of all patients had evidence of >50% atherosclerotic stenosis in 1, 2, or 3 coronary arteries. CONCLUSIONS: The prevalence of CAD in black African stroke patients is significantly higher than has been documented in the general nonstroke black population as well as in stroke patients. Black stroke patients may have a risk for CAD similar to that of their white counterparts.

Erythrocyte magnesium concentration as an index of magnesium status: a perspective from a magnesium supplementation study.

We investigated the utility of erythrocyte magnesium concentrations as an index of magnesium status. Calculated from the analytical and biological variation, the critical difference, i.e. the difference between results from serial specimens before they can be said to be statistically different, was 22.4% (P<0.05). Magnesium supplementation of 250 mg/day for 3 weeks in 20 women with an erythrocyte magnesium concentration less than the 15th percentile of a population sample (n=219), resulted in an increase in erythrocyte magnesium concentration of only 1.6%. We therefore conclude that sequential erythrocyte magnesium measurements are not useful for the monitoring of individual changes in magnesium intake and status.

Comparison of three different plasma homocysteine assays with gas chromatography-mass spectrometry.

BACKGROUND: Various methods are available to measure plasma total homocyst(e)ine (tHcy) concentrations, but whether plasma tHcy assays may be used interchangeably is not known. METHODS: Results from three different methods [HPLC with fluorescence detection, enzyme immunoassay (EIA), and fluorescence polarization immunoassay (FPIA)] to determine fasting (n = 163) and post-methionine load (n = 80) plasma tHcy concentrations were compared with those obtained by gas chromatography-mass spectrometry (GC-MS). Difference plots on non-transformed and log-transformed data were used to assess the agreement between HPLC and GC-MS, EIA and GC-MS, and FPIA and GC-MS. RESULTS: The closest agreement between methods was observed between GC-MS and FPIA for fasting tHcy concentrations, with 95% of the FPIA values between 19% above and 24% below the corresponding GC-MS results. Post-methionine load tHcy concentrations measured by EIA showed the least agreement with GC-MS, with 95% of values measured by EIA ranging between 52% above and 16% below the GC-MS values. With respect to GC-MS, the above-mentioned methods showed a negative bias for fasting tHcy concentrations, but a positive bias for both immunoassays for post-methionine load tHcy concentrations. CONCLUSIONS: The agreement among methods is insufficient to allow them to be used interchangeably. The intermethod differences emphasize the need for standardization of plasma tHcy assays.

Genetic control of lipoprotein(a) concentrations is different in Africans and Caucasians.

Lipoprotein(a) (Lp(a)) represents a quantitative trait in human plasma associated with atherothrombotic disease. Large variation in the distribution of Lp(a) concentrations exists across populations which is at present unexplained. Sib-pair linkage analysis has suggested that the apo(a) gene on chromosome 6q27 is the major determinant of Lp(a) levels in Caucasians. We have here dissected the genetic architecture of the Lp(a) trait in Africans (Khoi San, South African Blacks) and Caucasians (Austrians) by family/sib-pair analysis. Heritability estimates ranged from h2 = 51% in Blacks, h2 = 61% in Khoi San, to h2 = 71% in Caucasians. Analysis by a variance components model also demonstrated that the proportion of the total phenotypic variance explained by genetic factors is smaller in Africans (65%) than in Caucasians (74%). Importantly the sib-pair analysis clearly identified the apo(a) gene as the major locus in Caucasians which explained the total genetic variance. In the African samples the apo(a) gene accounted for only half the genetic variance. Together with previous results from population studies our data indicate that genetic control of Lp(a) levels seems to be distinctly different between Africans and Caucasians. In the former genetic factors distinct from the apo(a) locus and also non-genetic factors may play a major role.

Folate status, homocysteine metabolism, and methylene tetrahydrofolate reductase genotype in rural South African blacks with a history of pregnancy complicated by neural tube defects.

The birth incidence of neural tube defects (NTDs) in South Africa is threefold to sixfold higher in rural compared with urban blacks. We investigated whether folate deficiency and aberrant homocysteine metabolism could explain the high NTD incidence in rural black populations. Plasma folate and total homocyst(e)ine (tHcy) concentrations were determined in apparently healthy rural black women (n = 107), rural black women with a history of pregnancy complicated by NTDs (n = 54), and urban blacks (n = 101). Methionine load tests were performed on the 54 women with a history of NTD-affected pregnancy and 54 controls matched for age and body mass. The presence of the 677C --> T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene was investigated in both groups by a polymerase chain reaction (PCR) of genomic DNA and HinfI digestion of the PCR product. Apparently healthy urban black women (n = 101) had a lower (P < .001) plasma folate concentration compared with rural black women (n = 107). Women with a history of NTD-affected pregnancy did not differ significantly from controls with respect to plasma folate, fasting homocyst(e)ine, methionine, and the post-methionine load increase in plasma homocyst(e)ine. More than 50% of both of the latter groups had a post-methionine load increase in plasma tHcy less than the fifth percentile as observed in a healthy white control group. No homozygotes for the 677C --> T mutation in the MTHFR gene were found in black mothers with NTD-affected offspring or controls. It is concluded that black urbanization is characterized by a diminished folate status that is paradoxically associated with a lower NTD birth incidence. Homozygosity for the 677C --> T mutation in the gene coding for MTHFR does not constitute a genetic risk factor for NTDs in blacks. No aberrant homocysteine metabolism could be demonstrated in black women with NTD-affected pregnancies.

Antioxidant vitamins and coronary artery disease risk in South African males.

Decreased antioxidant-vitamin nutritional status may increase lipid peroxidation and susceptibility of low-density lipoprotein (LDL) to oxidative modification. The aim of this study was to evaluate the vitamin nutritional status of coronary artery disease (CAD) patients and to assess the risk of CAD related to each individual antioxidant vitamin. The study was performed as a case-control study with 41 patients with angiographically demonstrated CAD and 41 apparently healthy age- and smoking status-matched controls. Plasma vitamin E, C and A concentrations were significantly decreased in CAD patients compared with controls (p < 0.001) after correcting for significant covariates. Per quartile decrease in vitamin A and E concentrations was associated with increased risk of CAD, even after adjusting for CAD risk factors, while per quartile decrease in vitamin C concentrations was not associated with significant CAD risk after adjusting for CAD risk factors. Decreased vitamin A and E concentrations are independently associated with increased risk of CAD independent from other CAD risk factors in white male South Africans and dietary intervention strategies are advocated.