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The functions, genetic variations and impact of apolipoprotein E on lipoprotein metabolism in general are placed in the context of clinical practice dealing with moderate dyslipidaemia as well as dysbetalipoproteinemia, a highly atherogenic disorder and lipoprotein glomerulopathy. Additional variants of apolipoprotein E and participation of apolipoprotein E in inflammation are of interest. The mostly favourable effects of apolipoprotein E2 as well as the atherogenic nature of apolipoproteinE4, which has an association with cognitive impairment, are confirmed. The contribution of remnant lipoproteins of triglyceride-rich lipoproteins, of which dysbetalipoproteinemia represents an extreme, is explored in atherosclerosis. Mimetic peptides may present new therapeutic approaches. Apolipoprotein E is an important determinant of the lipid profile and cardiovascular health in the population at large and can precipitate dysbetalipoproteinemia and glomerulopathy. Awareness of apolipoprotein E polymorphisms should improve medical care.

Background: There is a shortage of data on the accuracy of statistical methods for the prediction of N-acetyltransferase 2 (NAT2) haplotypes in the mixed ancestry population of the Western Cape. Objective: This study aimed to identify the NAT2 haplotypes and assess the accuracy of PHASE version 2.1.1 in assigning NAT2 haplotypes to a mixed ancestry population from the Western Cape. Methods: This study was conducted between 2013 and 2016. The NAT2 gene was amplified and sequenced from the DNA of 100 self-identified mixed ancestry participants. Haplotyping was performed by molecular and computational techniques. Agreement was assessed between the two techniques. Results: Haplotypes were assigned to 93 samples, of which 67 (72%) were ambiguous. Haplotype prediction by PHASE demonstrated 94.6% agreement (kappa 0.94, p 0.001) with those assigned using molecular techniques. Five haplotype combinations (from 10 chromosomes) were incorrectly predicted, four of which were flagged as uncertain by the PHASE software. Only one resulted in the assignment of an incorrect acetylation phenotype (intermediate to slow), although the software flagged this for further analysis. The most common haplotypes were NAT2*4 (28%) followed by NAT2*5B (27.4%), NAT2*6A (21.5%) and NAT2*12A (7.5%). Four rare single nucleotide variants (c.589CT, c.622TC, c.809TC and c.387CT) were detected. Conclusion: PHASE accurately predicted the phenotype in 92 of 93 samples (99%) from genotypic data in our mixed ancestry sample population, and is therefore a suitable alternative to molecular methods to individualise isoniazid therapy in this high burden tuberculosis setting.

Background High density lipoprotein cholesterol (HDL-C) concentration correlates inversely with atherosclerotic cardiovascular disease (ASCVD) risk and is included in risk calculations. Endothelial lipase (EL) is a phospholipase that remodels HDL. Deficiency of EL due to mutations in its gene, LIPG, is associated with hyperalphalipoproteinemia. The effects of EL on HDL function and ASCVD risk remain poorly understood. Objectives To determine whether hyperalphalipoproteinemia due to EL deficiency is protective against ASCVD. Methods We identified LIPG variants amongst patients with severe hyperalphalipoproteinemia (HDL-C >2.5 mmol/L) attending a referral lipid clinic in the Western Cape Province of South Africa. We analysed the clinical and biochemical phenotypes amongst primary hyperalphalipoproteinemia cases (males HDL-C >1.6 mmol/L; females HDL-C >1.8 mmol/L) due to LIPG variants, and the distribution of variants in normal and hyperalphalipoproteinemia ranges of HDL-C. Results 1007 patients with HDL-C concentration ranging from 1.2 to 4.5 mmol/L were included. Seventeen females had primary hyperalphalipoproteinemia. Vascular disease was prominent, but not associated with HDL-C concentration, LDL-C concentration or carotid artery intima media thickness. Two novel and three known LIPG variants were identified in severe hyperalphalipoproteinemia. Four additional variants were identified in the extended cohort. Two common variants appeared normally distributed across the HDL-C concentration range, while six less-common variants were found only at higher HDL-C concentrations. One rare variant had a moderate effect. Conclusion Hyperalphalipoproteinemia due to LIPG variants is commoner in females and may not protect against ASCVD. Use of current risk calculations may be inappropriate in patients with hyperalphalipoproteinemia due to EL deficiency. Our study cautions targeting EL to reduce risk.

MPV17-related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non-consanguineous Black South African heritage. Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in 2 unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122-1/38) with an estimated newborn incidence of 1 in 18 496 (95% CI; 1/59 536-1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterized severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive genetic disease caused by mutations in the NPC1 and NPC2 genes with an estimated incidence of 1:120 000 live births. The clinical presentations vary across the ages. Children present with visceral symptoms related to cholesterol accumulation in the liver and adults have predominantly neuropsychiatric features such as dementia. However, vertical supranuclear gaze palsy can be present from the first year of life and is a strong feature in the diagnosis of NPC, which can be confirmed by a skin biopsy. A 36-year-old female with long-standing depression was referred for an evaluation of dystonia. She had progressive cognitive decline, dysarthria, dysphonia, dystonia of the trunk and limbs, ataxia and supranuclear gaze palsy. A similar course of illness affected her brother. Her parents were first cousins. She had positive Filipin stain of fibroblasts cultured from her skin biopsy, confirming the diagnosis of NPC. Miglustat, the approved drug for treatment, was not accessible. She had been on simvastatin since diagnosis, with a poor response, and had ongoing severe cognitive and physical disability. There are few conditions that present with neuropsychiatric symptoms and supranuclear gaze palsy. This patient had been managed as chronic depression with psychosis since her teenage years and her diagnosis was reviewed only when she had developed dystonia. Supranuclear gaze palsy is an early diagnostic clinical clue that could be present from infancy and should be sought in patients with neurocognitive presentations.

Many attempts have been made to define and reconstruct the most plausible ecological and dietary niche of the earliest members of the human species. While earlier models emphasise big-game hunting in terrestrial, largely savannah environments, more recent scenarios consider the role of marine and aquatic foods as a source of polyunsaturated fatty acids (PUFA) and other brain-selective nutrients. Along the coast of southern Africa, there appears to be an association between the emergence of anatomically modern humans and accumulation of some of the earliest shell middens during the Middle Stone Age (200–40 ka). Fragmentary fossil remains classified as those of anatomically modern humans, along with marine food residues and numerous material cultural indicators of increased social and behavioural complexity have been recovered from coastal sites. In this paper, new information on the nutrient content of marine and terrestrial foods available to early modern humans in the southwestern Cape is presented and compared with existing data on the nutritional value of some wild plant and animal foods in Africa. The results suggest that coastal foraging, particularly the collection of abundant and predictable marine molluscs, would have allowed early modern humans to exploit some of the richest and most accessible sources of protein, micronutrients and longer-chain omega-6 and omega-3 fatty acids. Reliable and accessible sources of omega-3 eicosapentaenoic and docosahexaenoic acid are considerably more restricted in terrestrial foods.

Advances in the causes of disorders of lipid metabolism, and effective intervention in atherosclerosis with medication, have increased the reliance on laboratory investigation in clinical practice. The conventional lipid profile, comprising fasting triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, suffices for screening persons at risk of atherosclerosis. Additionally, lipoprotein (a) measurement enhances risk assessment and could explain atherosclerosis with a desirable lipid profile. Certain rare disorders in sterol and fatty acid metabolism do not alter the conventional lipid profile. Non-fasting samples are gaining popularity, as the triglycerides, although mildly increased, signify atherogenic lipoprotein remnant accumulation. Apoprotein A1 (apo A1) and apo B concentrations parallel HDL cholesterol and LDL cholesterol, respectively, and are of value in disorders of these lipoproteins. In severe dyslipoproteinaemia, special investigations establish the cause of the disease and may allow selection of better treatment. In such cases, not only apoprotein concentrations, but also enzyme or cell function, as well as genetic investigations, are relevant. The most important genetic disorders to recognise are familial hypercholesterolaemia, dysbetalipoproteinaemia and chylomicronaemia. Expertise in lipidology is limited in South Africa, but specialist centres can provide clinical and laboratory support to ensure best management of severe disorders.

ObjectiveLomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of lomitapide.MethodsExisting lipid-lowering therapy, including apheresis, was to remain stable from Week −6 to Week 26. Lomitapide dose was escalated on the basis of individual safety/tolerability from 5 mg to 60 mg a day (maximum). The primary endpoint was mean percent change in LDL-C from baseline to Week 26 (efficacy phase), after which patients remained on lomitapide through Week 78 for safety assessment and further evaluation of efficacy. During this latter period, apheresis could be adjusted. We analysed the impact of apheresis on LDL-C reductions in patients receiving lomitapide.ResultsOf the 29 patients that entered the efficacy phase, 18 (62%) were receiving apheresis at baseline. Twenty-three patients (13 receiving apheresis) completed the Week 26 evaluation. Of the six patients who discontinued in the first 26 weeks, five were receiving apheresis. There were no significant differences in percent change from baseline of LDL-C at Week 26 in patients treated (−48%) and not treated (−55%) with apheresis (p = 0.545). Changes in Lp(a) levels were modest and not different between groups (p = 0.436).ConclusionThe LDL-C lowering efficacy of lomitapide is unaffected by lipoprotein apheresis.

Background. Criteria for labelling infant feeds as suitable for the dietary management of cow’s milk protein allergy (CMPA) rely on proving the hypoallergenicity of such feeds or clinical studies showing that the feeds are tolerated by 90% of children with proven CMPA. South African (SA) labelling legislation does not indicate what testing is necessary to prove hypoallergenicity. Objectives. To evaluate all extensively hydrolysed cow’s milk formulas and amino acid-based formulas available in SA for residual allergen content, protein size and amino-acid content. Results. All amino-acid and extensively hydrolysed formulas were found to be similar in composition, with no residual cow’s milk allergens detectable by enzyme-linked immunosorbent assay. Furthermore, proteins were absent and only small molecules in the size range of amino acids and possibly of very small oligopeptides were detected. Conclusions. These findings indicate that the formulas are extremely likely to be compliant with the definition of hypoallergenicity as tolerance in 90% of proven sufferers from cow’s milk allergy. The formulas may therefore be labelled as suitable for the dietary management of infants with CMPA.

Epidemiological evidence suggests cardiovascular benefits from the consumption of alcoholic beverages, but corroboration by functional and outcome studies is still outstanding. Non-invasive functional tests on the brachial arteries of healthy volunteers were performed before and for two hours after consuming red wine. Brachial artery dimensions were determined by ultrasound at baseline, 30, 60 and 120 min. Flow-mediated dilatation (FMD) was similarly assessed. Putative minimum and maximum lumen diameters were determined after ice immersion and sublingual trinitroglycerine (TNG) at baseline and 60 min after wine consumption. Sixteen subjects had a mean resting brachial artery diameter of 3.84 mm, which significantly increased with wine to 4.44 mm at 30 min, 4.39 mm at 60 min and 4.49 mm at 120 min. The calculated blood flow rates during the study did not differ significantly over the measured intervals. The baseline mean diameter with TNG was not significantly different from the dilation with wine. The vasoconstrictor response varied, with a -2.6 ± 2.9% change with wine, compared with the baseline diameter. There was appreciable variation of the diameter relative to the range found with ice and TNG. The calculated FMDs (% changes) for the study were 10.8, 6.1, 5.6 and 7.5, indicating statistically significant effects of wine (p < 0.0001). The authors conclude that red wine consumption leads to beneficial arterial effects that may relate to different doses or other mechanisms than FMD. Further studies need to be done to discriminate between the effects of alcohol and phenolic compounds on vascular function.

Letter by Nutten et al. on article by Levin et al . (Levin ME, Blackhurst DM, Kirstein F, Kok D, van der Watt GF, Marais AD. Residual allergenicity of amino acid-based and extensively hydrolysed cow’s milk formulas. S Afr Med J 2017;107(9):763-767. S Afr Med J 2017;107(3):258-263. https://doi.org/10.7196/SAMJ.2017.v107i9.12137); and response by Levin et al .

To review publications in the English literature over the past 18 months relating to the management of homozygous familial hypercholesterolaemia.Experience with plasmapheresis has been summarized, guidelines are being introduced to enhance patient care and registries are under consideration to improve analysis of management in this rare but serious disorder. Liver transplantation has been reviewed for its biochemical efficacy, but still does not ensure freedom from vascular complications. For patients without access to plasmapheresis, there is now evidence that high-dose statins do improve the prognosis, but combination therapy with additional agents should still be considered for better outcome. Promising new agents that inhibit LDL production by limiting apolipoprotein B100 synthesis by means of antisense oligonucleotides (mipomersen) or by inhibition of microsomal triacylglycerol transfer protein (lomitapide) have made significant additional LDL reduction possible but are associated with hepatic fat accumulation and long-term safety data is still required. Several other lipid modulating agents and gene therapy are still being explored.The management of homozygous familial hypercholesterolaemia by pharmacological means is improving with agents that limit lipoprotein production but plasmapheresis, generally in combination with additional pharmacological treatment, remains the proven option. Liver transplantation is now less likely to be undertaken owing to improved pharmacological options and prognosis.

Background : Pregnancy is associated with increases in fasting triglycerides and total cholesterol.1 ApoE isoforms are known to influence the concentration of cholesterol, with apoE2 homozygosity lowering and apoE4 homozygosity raising the cholesterol concentration compared with E3 homozygosity.2 The lipid profiles ApoE status and prevalence of small dense LDL species were evaluated for subjects attending an antenatal clinic. Results : Samples from 690 women aged between 16 and 42 years of age were analyzed during and after pregnancy. The fasting plasma triglyceride concentration (in mmol/L) was significantly higher in pregnancy (median = 1.5, IQR 1.0-2.0 vs median = 0.6, IQR 0.5-0.8 respectively, p < 0.0001). Similarly, the total cholesterol (in mmol/L) was increased during pregnancy (median=4.1, IQR 3.6-4.7 vs median 3.5, IQR 3.1-3.5, respectively p=0.0167). The median LDL cholesterol and HDL cholesterol did not change. Higher proportions of small density LDL species were seen during pregnancy compared to after pregnancy. The distribution of the LDL species during pregnancy and 6 weeks post-partum were significantly different p

Phytosterolaemia,1 causing severe atherosclerosis,2 illustrates the stringent requirements for sterols in membranes and the impact of low-density lipoprotein (LDL) receptor on metabolism, but is not associated with malformations seen with sterol biosynthetic defects. Membranes contain hopanoids3 in bacteria and a range of phytosterols in plants, mostly campesterol and beta-sitosterol. Animal cell membranes contain cholesterol. The rate-controlling step in sterol biosynthesis is the formation of mevalonic acid by hydroxymethylglutaryl coenzyme A reductase that can be inhibited by statins. During biosynthesis six isopentenyl units form a 30-carbon molecule. Demethylation, double-bond reduction and the creation of one final unsaturated bond deliver cholesterol. Phytosterols are synthesised similarly but retain methyl or ethyl moieties or double bonds. Cholesterol evolved …

Click on the link to view.S Afr Med J 2018;108(9):707

Mutations in the low-density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia. In homozygous familial hypercholesterolemia, both genes for the LDL- receptor are mutated and LDL levels are markedly elevated. High-density lipoprotein cholesterol concentration is often reduced and lipoprotein(a) levels are high when corrected for apolipoprotein(a) isoforms. Cutaneous and tendinous xanthomata develop in childhood and are the most common reason for initial presentation. The diagnosis can be confirmed by analysis of LDL-receptor genes or studies of LDL receptor function in cultured cells. Severe aortic and coronary atherosclerosis usually occurs within the first or second decades of life. Left ventricular outflow tract obstruction may be at the level of the aortic valve or the supravalvar aorta. Treatment for the hyperlipidemia is with plasmapheresis, high-dose statins, and ezetimibe. Liver transplantation reverses the metabolic defect but requires chronic immunosupression, and rejection may still occur. Liver transplantation is indicated if cardiac transplantation becomes necessary. Portocaval shunt may still play a role in patients with coronary artery disease who do not have access to plasmapheresis. Gene therapy is currently not practicable but is being actively developed.

Glucocorticoids have multiple therapeutic uses, but their impact on lipid metabolism and cardiovascular disease risk is not always considered during long-term treatment. Genetic variations, environmental factors and the reasons for glucocorticoid treatment all influence the lipid profile and atherosclerosis. Responses to glucocorticoid treatment may therefore be variable and unpredictable. Despite the frequency with which pharmacological doses of glucocorticoids are used, surprisingly few publications examine their effects on lipid metabolism and atherosclerosis. Patients managed with glucocorticoids should have their cardiovascular risk assessed, especially if long-term treatment is planned. While some apparent favourable changes have been reported in high-density lipoprotein metabolism, very-low-density lipoprotein and low-density lipoprotein responses seem unfavourable. The impact of glucocorticoids on atherosclerosis, which is often viewed as an inflammatory process, is unclear. Glucocorticoid treatment should be undertaken for appropriate indications, but in some instances special attention should be given to management of dyslipidaemia, as long-term survivors of treatment are likely to encounter atherosclerosis.

Atherosclerosis is strongly associated with dyslipoproteinaemia, and especially with increasing concentrations of low-density lipoprotein and decreasing concentrations of high-density lipoproteins. Its association with increasing concentrations of plasma triglyceride is less clear but, within the mixed hyperlipidaemias, dysbetalipoproteinaemia (Fredrickson type III hyperlipidaemia) has been identified as a very atherogenic entity associated with both premature ischaemic heart disease and peripheral arterial disease. Dysbetalipoproteinaemia is characterized by the accumulation of remnants of chylomicrons and of very low-density lipoproteins. The onset occurs after childhood and usually requires an additional metabolic stressor. In women, onset is typically delayed until menopause. Clinical manifestations may vary from no physical signs to severe cutaneous and tendinous xanthomata, atherosclerosis of coronary and peripheral arteries, and pancreatitis when severe hypertriglyceridaemia is present. Rarely, mutations in apolipoprotein E are associated with lipoprotein glomerulopathy, a condition characterized by progressive proteinuria and renal failure with varying degrees of plasma remnant accumulation. Interestingly, predisposing genetic causes paradoxically result in lower than average cholesterol concentration for most affected persons, but severe dyslipidaemia develops in a minority of patients. The disorder stems from dysfunctional apolipoprotein E in which mutations result in impaired binding to low-density lipoprotein (LDL) receptors and/or heparin sulphate proteoglycans. Apolipoprotein E deficiency may cause a similar phenotype. Making a diagnosis of dysbetalipoproteinaemia aids in assessing cardiovascular risk correctly and allows for genetic counseling. However, the diagnostic work-up may present some challenges. Diagnosis of dysbetalipoproteinaemia should be considered in mixed hyperlipidaemias for which the apolipoprotein B concentration is relatively low in relation to the total cholesterol concentration or when there is significant disparity between the calculated LDL and directly measured LDL cholesterol concentrations. Genetic tests are informative in predicting the risk of developing the disease phenotype and are diagnostic only in the context of hyperlipidaemia. Specialised lipoprotein studies in reference laboratory centres can also assist in diagnosis. Fibrates and statins, or even combination treatment, may be required to control the dyslipidaemia.

Congenital analbuminaemia, a rare disorder associated with defective albumin synthesis, is characterised by hyperlipidaemia. Administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGRI) to analbuminaemic rats have demonstrated no significant effect on plasma lipids, however no published information regarding HMGRI treatment could be found in human subjects. The efficacy, safety and tolerability of Simvastatin was thus investigated in 2 South African patients with analbuminaemia, a 21 year old Caucasian male (H-B) and a 61 year old black male (A-K). In the case of A-K, the lipid profile responded predictably but H-B responded less that expected from general experience with Simvastatin. Both subjects, however, experienced a three- to five-fold increase in creatine kinase. The use of HMGRI's should thus be used cautiously in these patients and it may be advisable to reserve treatment for secondary prevention.

Small, dense LDL particles have been linked to atherosclerosis, often in a cluster of risk factors and affecting approximately 20% of adults. Over the past year, studies confirmed that small dense LDL is an autosomal dominant trait, influenced mainly by hypertriglyceridaemia and obesity, insulin resistance and diabetes mellitus and some incompletely investigated genetic loci. Compositional and functional differences have been observed in small LDL. Evidence is emerging that lifestyle as well as pharmacological intervention can modulate LDL size, but there is no proof yet that this is of clinical benefit.

4but the collective term now includes arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), molybdenum (Mo), nickel (Ni), vanadium (V) and zinc (Zn). Some interest also exists in aluminium, cobalt, strontium and other rarer metals. Potassium, calcium and magnesium are expected in wine because of their high intracellular content. Physiologic roles are known for Fe (haem moeities of haemoglobin and cytochromes), Cu (amine oxidases, caeruloplasmin, dopamine hydrolase and collagen synthesis), Mn (superoxide dismutase), Zn (protein synthesis, stabilisation of DNA and RNA) with low requirements of Cr (glucose homeostasis). Other heavy metals ions are not believed to be essential to health, even in trace amounts.

Abstract Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are the drugs of choice in heterozygous familial hypercholesterolemia (FH), which has a high risk of ischemic heart disease. An open-label study was conducted to test the efficacy and safety of atorvastatin, a new synthetic HMG-CoA reductase inhibitor in proven FH. After a 4-week placebo phase, 22 subjects were randomized to either 80 mg atorvastatin at night (n=11) or 40 mg twice a day for 6 weeks. The two dosage groups were well matched and had no difference in lipoprotein responses. After 6 weeks, the LDL cholesterol concentration was reduced by 57%, from 8.16±1.15 to 3.53±0.99 mmol/L ( P P P P

South Africa, especially the Caucasian part of the population, has one of the highest incidences of familial hypercholesterolemia in the world. The founder effect in this region has led to this high incidence and to a limited number of mutations in the low-density lipoprotein-receptor gene. This chapter describes current situation concerning the management of familial hypercholesterolemia in South Africa.

The prevalence of cardiovascular disease is projected to be 38.7% for the USA in 2020, including coronary heart disease at 8.6% and stroke at 3.6%. In South Africa (SA), premature deaths due to heart and blood vessel diseases in people of working age (35 - 64 years) have been predicted to increase by 41% between 2007 and 2030, with enormous negative economic impact. Atherosclerosis underlies much of the pathogenesis, which involves risk factors including dyslipidaemia. Secondary dyslipidaemia associated with diabetes mellitus, hypothyroidism, chronic renal disease, cholestasis, nephrotic syndrome, alcohol excess, drugs such as thiazide diuretics and antiretroviral agents may respond to treatment of underlying causes, but residual dyslipidaemia may in such cases be due to primary disorders of metabolism. Primary dyslipidaemias are uncommon and to a large extent underdiagnosed, especially in the black population of SA, reflecting a lack of clinical and laboratory awareness or expertise. Specific diagnoses enable effective intervention in the patients as well as the families.To assess the burden and prevalence of dyslipidaemia in the SA black population at Dr George Mukhari Hospital in the north region of Gauteng.A retrospective data analysis of 12-month lipid profiles comprising triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol and directly measured low-density lipoprotein (LDL) cholesterol (LDLC).There were 24 656 requests for 6 348 patients. The lipid cut-off levels were somewhat arbitrary but were based on the commonly used decision-making levels in the treatment guidelines. Severe hypercholesterolaemia (gt;7 mmol/L) was seen in 299 (4.7%) patients and extreme hypercholesterolaemia (gt;12 mmol/L) was seen in 30 (0.5%) patients. LDLC (gt;5 mmol/L) occurred in 80 (1.3%) patients and gt;10 mmol/L in 19 (0.3%) patients. A predominant triglyceride problem was seen in 578 (9.1%) patients with TG (gt;2 mmol/L) and TC (lt;5 mmol/L), whereas moderate hypertriglyceridaemia (gt;5 mmol/L) was present in 113 (1.8%) patients, and more severe hypertriglyceridaemia (gt;10 mmol/L) in 10 (0.2%). TC (gt;5 mmol/L) with LDL (gt;3 mmol/L) but TG in the normal range was seen in 369 (5.8%) patients, indicating a cholesterol-predominant problem. In contrast, LDLC (gt;3 mmol/L) and TG (gt;1.7 mmol/L) was seen in 249 (3.87%) representing mixed hyperlipidaemia. Paediatric patients with severe dyslipidaemia mostly suffered from nephrotic syndrome.A significant burden and a high prevalence of dyslipidaemias were present in adults in whom a monogenic disorder should be considered. The extent and severity of dyslipidaemia justify a special clinic and laboratory to ensure accurate diagnosis with effective intervention for patients and their families.

Background/Aims: This study sought to determine whether excess hepatic iron potentiates liver injury in the methionine choline-deficient (MCD) model of non-alcoholic fatty liver disease (NAFLD). Methods: Iron-loaded rats were fed either MCD or control diets [MCD diet plus choline bitartrate (2 g/kg) and dl-methionine (3 g/kg)] for 4 and 12 weeks, after which liver pathology, hepatic iron, triglyceride, lipid peroxidation products and hydroxyproline (HYP) levels and serum alanine aminotransferase (ALT) levels were evaluated. Results: Iron supplementation in MCD animals resulted in histologic evidence of hepatic iron overload at 4 and 12 weeks and a 14-fold increase in hepatic iron concentration at 12 weeks (P

Homozygous familial hypercholesterolemia is a rare disorder resulting in severe premature atherosclerosis. Drug therapy was previously viewed as inadequate for control of the dyslipidemia, so portacaval shunting, plasmapheresis, and liver transplantation were undertaken to treat this condition. Despite these drastic measures, additional cholesterol-lowering treatment may still be required. Furthermore, there is a need for pharmacologic control until additional measures can be undertaken. The statins, an evolving class of cholesterol-modifying drugs, represent a significant development in the treatment of homozygous familial hypercholesterolemia. The experience with statins in this condition is limited, but some insight into their utility has been gained from studies reviewed in this article. It is recommended that high doses of statins be used in combination with other lipid-modifying strategies for the best control of the dyslipidemia of homozygous familial hypercholesterolemia.

Recent primary prevention trials demonstrated that cardiovascular morbidity and mortality benefits are not accompanied by adverse effects on overall mortality and morbidity in cohorts representing plasma cholesterol concentrations observed in the bulk of coronary artery disease. During the past year, further analyses of the West of Scotland Coronary Prevention Study have indicated that benefit requires a 25% reduction of LDL cholesterol and that such treatment is not very expensive when focussed on selected high-risk individuals. The Air Force/Texas Coronary Artery Prevention Study indicated that benefit is seen in individuals with even lower plasma lipid concentration. Although current treatment with lifestyle and lipid modifying drug management is successful in primary prevention, the unpredictable nature of coronary artery disease and the cost of drugs mitigate against direct application of drug management in persons with relatively low risk, but selective treatment should be undertaken in very high-risk settings. Future studies need to examine more specific at risk cohorts, test better targeted lipoprotein modification, test more risk factors and also examine whether changes in vascular function or markers of inflammation will predict a better outcome.

Preclinical and clinical data on atorvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, indicate that it has superior activity in treating a variety of dyslipidemic disorders characterized by elevations in low-density lipoprotein cholesterol (LDL-C) and/or triglycerides. Results for patients randomized in early efficacy and safety studies were combined in one database and analyzed. This analysis included a total of 231 atorvastatin-treated patients (131 with hypercholesterolemia (HC), 63 with combined hyperlipidemia (CH), 36 with hypertriglyceridemia (HTG), and 1 with hyperchylomicronemia (Fredrickson Type V)). Patients were treated with a cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step 1 diet or a more rigorous diet) and either 2.5, 5, 10, 20, 40, or 80 mg/day of atorvastatin or placebo. Efficacy was based on percent change from baseline in total cholesterol, total triglycerides, LDL-C, very low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apo B), and non-HDL-C/HDL-C. Safety was assessed in all randomized patients. Atorvastatin seemed to preferentially lower those lipid and lipoprotein component(s) most elevated within each dyslipidemic state: LDL-C in patients with HC, triglycerides and VLDL-C in patients with HTG, or all 3 in patients with CH. Atorvastatin was well-tolerated with a safety profile similar to other drugs in its class.

We report the results of a two center study on the use of the HMG Co A reductase inhibitor, simvastatin, in 44 patients suffering from familial hypercholesterolemia or from primary hypercholesterolemia of unknown etiology. The study included two separate phases: Phase I was part of a multicenter, 4-week, placebo-controlled trial; phase II was a 6-month, open extension trial, the object of which was to reduce low density lipoprotein (LDL) cholesterol levels to below the 50th percentile by increasing the dose of simvastatin, by the use of additional lipid-lowering medication, or both. Our phase I results were commensurate with those reported for the entire international cohort of 272 patients, indicating a clear dose-response relationship, with approximately 75% of the maximum reduction in LDL-C levels being achieved with 20 mg/day and over 90% of the maximum being achieved with 40 mg of simvastatin per day. In the open extension trial, the results from the 2 centers were essentially similar. Total cholesterol fell by 29% on the 20 mg/day dose and by 34% on the full dose of 40 mg/day. LDL-C levels were reduced by 40% on the 40 mg/day schedule, and triglycerides also fell to between 20% and 40% below baseline values. HDL-C concentration rose by 14% and 17.6%. The effects of simvastatin were uniform, both within and between the two cohorts. The addition of cholestyramine caused a further substantial reduction in LDL-cholesterol to below 55% of the initial value in four patients, whereas bezafibrate further enhanced the fall in triglycerides and the increase in high-density lipoprotein cholesterol, but had only a slight effect on LDL-C levels. Adverse reactions included asymptomatic increases in plasma creatine kinase activity, generally associated with previous physical exertion, and transient rises in transaminase levels. In one patient with a history of alcoholic excess, transaminase levels were persistently greater than normal. These results indicate that the HMG Co A reductase inhibitor, simvastatin, is a powerful therapeutic agent for the lowering of plasma cholesterol levels in patients with genetic hypercholesterolemia.

The European Society of Cardiology together with the European Atherosclerosis Society published updated dyslipidaemia guidelines in 2011. SA Heart and the Lipid and Atherosclerosis Society of Southern Africa officially adopt these guidelines. This statement adapts aspects of the guidelines to the South African situation. Using the updated Framingham risk charts, interventional strategies are based according to the cardiovascular risk score and low-density lipoprotein cholesterol (LDL-C) levels. The Framingham risk score refers to the 10-year risk of any cardiovascular event, and includes four categories of risk. Treatment targets are those of the European guidelines. The LDL-C goal is 1.8 mmol/l for the very high-risk group (>30%), 2.5 mmol/l for the high-risk group (15 - 30%), and 3 mmol/l for those below 15% risk. Intensive management of dyslipidaemia in South Africa will significantly reduce the cardiovascular disease health burden.