The diagnosis and management of familial hypercholesterolaemia.

Familial hypercholesterolaemia is a clinical entity comprising high concentrations of low density lipoproteins, tendinous deposition of cholesterol in a large proportion of affected subjects, and a propensity for the development of atherosclerosis and its complications in the coronary arteries. The aim of this review is to integrate publications with clinical experience into a concise profile of the disorder and its management. In less than a century this disease has been recognised, its lipoprotein derangement identified and numerous causal mutations have been detected. Although the phenotype is most commonly due to the occurrence of mutations in the low density lipoprotein receptor, defects in the apolipoprotein B100 may result in a similar phenotype. The same phenotype has also been linked to a gene and its product, PCSK9 and NARC1, that may be involved in the regulation of cholesterol in the cell. In the past few decades statins, by inhibiting cholesterol synthesis at the rate-limiting enzyme (hydroxymethylglutaryl coenzyme A reductase) have been developed and proven safe and effective in reducing the low density lipoprotein cholesterol, promoting regression and reducing mortality and morbidity. Additionally, advances in imaging techniques are allowing non-invasive insights into the impact of the disease on atherosclerosis. For these reasons there should be a high index of suspicion for this treatable condition in which genetic therapy and further modulation of atherosclerosis can be expected in the future.

Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia.

Fasting plasma mevalonic acid (MVA), an indicator of in vivo cholesterol synthesis, was measured in 35 patients with familial hypercholesterolaemia (FH) of whom 7 were treated with pravastatin 10-40 mg/day, 7 with simvastatin 10-40 mg/day and 21 with atorvastatin 80 mg/day. Reductions in low density lipoprotein (LDL) cholesterol and MVA on maximal dose therapy differed significantly between the three drugs: 34.7%, 42.9% and 54.0% (P = 0.0001), and 31.6%, 48.9% and 58.8% (P = 0.004), respectively. Patients on atorvastatin were subdivided according to whether their reduction in LDL cholesterol on treatment was above or below the mean percentage change for the whole group. Basal values of LDL cholesterol did not differ significantly, but above average responders had a significantly higher mean pre-treatment level of MVA (6.2 +/- 0.60 vs. 4.3 +/- 0.61 ng/ml, P < 0.05) than below average responders. When all three drug groups were pooled above average responders showed a significantly greater absolute decrease in MVA on treatment than below average responders (3.85 +/- 0.48 vs. 2.33 +/- 0.40 ng/ml, P < 0.05). However, there was no significant correlation between the magnitude of the decreases in LDL cholesterol and MVA. These findings suggest that FH patients who responded well to statins had a higher basal level of plasma MVA, i.e. a higher rate of cholesterol synthesis, which was more susceptible to pharmacological inhibition. The more marked cholesterol lowering effect of atorvastatin 80 mg/day presumably reflects, at least in part, its ability to inhibit HMG-CoA reductase to a greater extent than maximal recommended doses of pravastatin and simvastatin of 40 mg/day.

Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.

Patients with homozygous familial hypercholesterolaemia (HoFH) have markedly elevated low density lipoprotein (LDL) cholesterol levels that are refractory to standard doses of lipid-lowering drug therapy. In the present study we evaluated the effect of atorvastatin on steady state concentrations of plasma lipids and mevalonic acid (MVA), as well as on 24-h urinary excretion of MVA in patients with well characterized HoFH. Thirty-five HoFH patients (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. The dose of atorvastatin was increased further to 120 mg/day in 20 subjects and to 160 mg/day in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mg/kg body wt per day. LDL cholesterol levels were reduced by 17% at the 40 mg/day and by 28% at the 80 mg/day dosage (P<0.01). Reduction in LDL cholesterol in the five receptor negative patients was similar to that achieved in the 30 patients with residual LDL receptor activity. Plasma MVA and 24-h urinary excretion of MVA, as markers of in vivo cholesterol synthesis, were elevated at baseline and decreased markedly with treatment. Urinary MVA excretion decreased by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (P<0. 01). There was a correlation between reduction in LDL cholesterol and reduction in urinary MVA excretion; those patients with the highest basal levels of MVA excretion and thus the highest rates of cholesterol synthesis having the greatest reduction in LDL cholesterol (r=0.38; P=0.02). Increasing the dose of atorvastatin to 120 and 160 mg/day did not result in any further reduction in LDL cholesterol or urinary MVA excretion suggesting a plateau effect with no further inhibition of cholesterol synthesis at doses of atorvastatin greater than 80 mg/day.

Three different schedules of low-density lipoprotein apheresis compared with plasmapheresis in patients with homozygous familial hypercholesterolemia.

PURPOSE: To determine the biochemical and clinical response of two patients with homozygous familial hypercholesterolemia to three different schedules of low-density lipoprotein apheresis compared with plasmapheresis. PATIENTS AND METHODS: Two female patients aged 17 years, both affected by homozygous familial hypercholesterolemia, underwent low-density lipoprotein apheresis using a dextran-sulfate/cellulose affinity column on successive twice-weekly, weekly, and biweekly schedules. Plasmapheresis was carried out only at biweekly intervals. Plasma lipids and apolipoproteins A1 and B were assayed before and after each procedure. Cardiac status was assessed before and after the study. RESULTS: On schedule 1 of apheresis, the immediate post-procedure low-density lipoprotein cholesterol levels declined to 60 mg/100 dL plasma. Quasi-steady-state values of low-density lipoprotein cholesterol and apolipoprotein B were also markedly reduced, with levels approaching the upper limits of normal for age and sex. This response was attenuated as the intervals between procedures were prolonged. No advantage of low-density lipoprotein apheresis over plasmapheresis was observed during the biweekly protocol except that after plasmapheresis high-density lipoprotein cholesterol levels declined by 50% or more compared with less than 10% after apheresis. The latter procedure, especially on schedules 1 and 2, caused an increase in the quasi-steady-state concentrations of both high-density lipoprotein cholesterol and apolipoprotein A1. Thus, mean low-density lipoprotein cholesterol/high-density lipoprotein cholesterol and apolipoprotein B/apo A1 ratios were reduced by more than three- to four-fold during twice-weekly apheresis. Other laboratory parameters remained stable throughout except for iron and hemoglobin levels, which were reduced with both plasmapheresis and apheresis. Xanthomas regressed significantly in the one patient who had not been treated prior to the current trial. Cardiac changes were minor in both patients. CONCLUSION: Low-density lipoprotein apheresis proved safe and effective on an accelerated protocol as well as during more conventional schedules. Owing to its simplicity, selectivity, and safety, apheresis using a dextran-sulfate/cellulose column is possibly the optimum means currently available for the extracorporeal removal of low-density lipoprotein cholesterol.

Severe hypertriglyceridaemia as a result of familial chylomicronaemia: the Cape Town experience.

Lipoprotein lipase deficiency causes severe hypertriglyceridaemia due to chylomicronaemia, and leads to recurrent and potentially life-threatening pancreatitis. This disorder can only be managed by dietary fat restriction as drugs are ineffective. We review the experience with familial chylomicronaemia in patients who attended the lipid clinics at Groote Schuur Hospital and Red Cross Children's War Memorial Hospital in Cape Town. Criteria for inclusion were an initial plasma triglyceride concentration of >15 mmol/l and a typical type I Fredrickson hyperlipidaemia pattern on plasma lipoprotein electrophoresis. A total of 29 patients were seen over 25 years. The mean age of presentation was 10 years, but ranged from 0 to 43 years. The modes of presentation differed: pancreatitis (N=16), eruptive xanthomata (N=2), coincidental detection of hypertriglyceridaemia (N=2), screening relatives (N=7), and after death from pancreatitis (N=1). Plasma triglycerides responded rapidly and dramatically to dietary fat restriction, and some patients sustained good control of the hyperlipidaemia. The onset of pancreatitis was earlier in patients of Indian ancestry, suggesting a genotype/phenotype interaction within this disorder. Genetic work-up indicated founder effects in the Afrikaner and Indian patients. Lipaemic plasma should be taken seriously at all ages, and necessitates work-up at specialised clinics where the diagnosis of chylomicronaemia or type I hyperlipidaemia facilitates appropriate dietary management that can prevent pancreatitis.

Statins in homozygous familial hypercholesterolemia.

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.

Plasma exchange for homozygous familial hypercholesterolaemia: the Cape Town experience.

Homozygous familial hypercholesterolaemia (FH) is a rare disorder having a greater frequency in populations with founder effects for the mutations in low density lipoprotein (LDL) receptors. It is characterized by early signs of cholesterol infiltrates with premature coronary artery disease and does not respond to conventional lipid-lowering therapy. Plasma exchange is an established mode of treatment which improves the biochemical abnormality and may allow reversal of the physical manifestations as well as favourably influencing the clinical course of the disease. The efficacy, safety and tolerability of this procedure is confirmed by our experience over the 15 years following the previous report. In a subset of these patients who have residual LDL receptor activity, further lowering of the plasma cholesterol concentration was achieved by adding simvastatin, an hydroxy-methylglutaryl coenzyme A reductase inhibitor. It is concluded that this combined approach may be of benefit in selected cases of homozygous FH undergoing regular plasmapheresis.

Fatal outcome of homozygous familial hypercholesterolaemia in a black patient. A case report.

A black patient with homozygous familial hypercholesterolaemia associated with ischaemic heart disease and a fatal outcome is described. The appearances of the coronary artery and aortic lesions on histological examination at autopsy were identical to those of typical atherosclerosis.

Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia.

Apheresis only partially controls raised low density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia, who usually respond poorly to lipid-lowering drugs. The efficacy and mechanism of action of a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, atorvastatin, was therefore investigated in seven homozygotes undergoing apheresis. One receptor-negative and six receptor-defective homozygotes undergoing plasma exchange or LDL apheresis every 2 weeks were studied during 2 months each on placebo and on atorvastatin 80 mg daily. Changes in plasma lipids and mevalonic acid, an index of cholesterol synthesis, were measured and the kinetics of the rebound of low density lipoprotein cholesterol and apolipoprotein B after apheresis were analyzed. All subjects had significant improvements on atorvastatin. Mean decreases in low density lipoprotein cholesterol were 31% greater both pre- and post-apheresis on atorvastatin compared with placebo, accompanied by a 63% decrease in mevalonic acid. Percentage changes in low density lipoprotein cholesterol and mevalonic acid were closely correlated (r = 0.89, P = 0.007). The mean production rates of low density lipoprotein cholesterol and apolipoprotein B were 21% and 25% lower, respectively, on atorvastatin than on placebo (P < 0.005 and <0.02) but changes in mean fractional clearance rates were not statistically significant. We conclude that atorvastatin enhances the efficacy of plasma exchange and low density lipoprotein apheresis in patients who lack low density lipoprotein receptors. This effect appears to be due to marked inhibition of cholesterol synthesis which results in a decreased rate of production of low density lipoprotein.

Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia.

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 < .001). The total cholesterol concentration decreased from 9.90 +/- 1.32 to 5.43 mmol/L (P < .001). HDL cholesterol concentration increased from 1.19 +/- 0.31 to 1.49 +/- 0.43 mmol/L (P < .001). Triglyceride concentrations decreased from 1.34 +/- 0.66 to 0.88 +/- 0.36 mmol/L (P < .01). Three subjects had single, transient increases of serum transaminase of up to twice the upper limit of normal. Apolipoprotein B concentration decreased significantly by 42%. Changes in apolipoproteins AI and (a) were not statistically significant. Nondenaturing gradient gel electrophoresis revealed increases in the size of smaller LDL particles in four subjects. Plasma fibrinogen concentration increased by 44%. The drug was well tolerated. One subject withdrew for personal reasons. Atorvastatin is a powerful and safe lipid-modifying agent for LDL cholesterol; it also modifies HDL cholesterol and triglyceride concentrations, and may suffice as a single agent for many subjects with heterozygous FH.

A 6-month trial of simvastatin (HMG-CoA reductase inhibitor) in the treatment of hypercholesterolaemia.

The aim of this study was to evaluate the long-term efficacy and tolerability of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin, over a 24-week period. Patients (108) with primary hypercholesterolaemia were clinically, haematologically and biochemically evaluated and established on a cholesterol-lowering diet. After a wash-out period free from other lipid-lowering drugs and a baseline period on placebo of 1 month each, 10 mg simvastatin was introduced at night. The dose was increased to 20 mg and 40 mg at 6 and 12 weeks' follow-up respectively if the total cholesterol (TC) level was still above 5.17 mmol/l. Follow-up took place every 6 weeks and included lipid, haematological, biochemical and clinical evaluation. A full ophthalmological evaluation was conducted at baseline and at 24 weeks' follow-up. Overall the TC level was reduced below the baseline level by 34.3% at week 18 of follow-up and 32.5% at week 24. Patients with higher initial TC levels showed greater TC lowering in response to simvastatin than did those with lower initial TC levels. A group of 45 patients was followed up for an additional 12 weeks after the end of the trial and maintained TC reductions similar to those at the end of the trial. Fourteen patients experienced adverse effects which were thought to be drug-related. One patient was withdrawn from the trial after developing conjunctivitis that proved to be related to the use of simvastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry.

The South African population harbors genes that are derived from varying degrees of admixture between indigenous groups and immigrants from Europe and the East. This study represents the first direct mutation-based attempt to determine the impact of admixture from other gene pools on the familial hypercholesterolemia (FH) phenotype in the recently founded Coloured population of South Africa, a people of mixed ancestry. A cohort of 236 apparently unrelated patients with clinical features of FH was screened for a common mutation causing familial defective apolipoprotein B-100 (FDB) and seven low-density lipoprotein receptor (LDLR) gene defects known to be relatively common in South Africans with FH. Six founder-type 'South African mutations' were responsible for FH in approximately 20% of the study population, while only 1 patient tested positive for the familial defective apolipoprotein B-100 mutation R3500Q. The detection of multiple founder-type LDLR gene mutations originating from European, Indian and Jewish populations provides direct genetic evidence that Caucasoid admixture contributes significantly to the apparently high prevalence of FH in South African patients of mixed ancestry. This study contributes to our knowledge of the biological history of this unique population and illustrates the potential consequences of recent admixture in populations with different disease risks.

Severe Hypertriglyceridaemia as a Result of familial Chylomicronaemia : the Cape Town Experience

Lipoprotein lipase deficiency causes severe hypertriglyceridaemia due to chylomicronaemia and leads to recurrent and potentially life-threatening pancreatitis. This disorder can only be managed by dietary fat restriction as drugs are ineffective.We review the experience with familial chylomicronaemia in patients who attended the lipid clinics at Groote Schuur Hospital and the Red Cross Children's War Memorial Hospital in Cape Town. The criteria for inclusion were an initial plasma triglyceride concentration of 15 mmol/L and a typical type I Fredrickson hyperlipidaemia pattern on plasma lipoprotein electrophoresis. A total of 29 patients were seen over 25 years. The mean age of presentation was 10 years; but ranged from from 0 to 43 years. The modes of presentation differed: pancreatitis (n=16); eruptive xanthomata (n=2); coincidental detection of hypertriglyceridaemia (n=2); screening relatives (n=7) and after death from pancreatitis (n=1). Plasma triglycerides responded rapidly and dramatically to dietary fat restriction and some patients sustained good control of the hyperlipidaemia.. The onset of pancreatitis was earlier in patients of Indian ancestry suggesting a genotype/phenotype interaction within this disorder. Genetic work-up indicated founder effects in the Afrikaner and Indian patients. Lipaemic plasma should be taken seriously at all ages and necessitates work-up at specialised clinics where the diagnosis of chylomicronaemia or type I hyperlipidaemia facilitates appropriate dietary management that can prevent pancreatitis