Diagnostic scoring for familial hypercholesterolaemia in practice

Purpose of review: Diagnostic scoring for familial hypercholesterolaemia (FH) can be used either to screen for possible FH or guide the selection of patients for genetic (DNA) testing. We review the published diagnostic criteria and discuss the options for future development. Recent findings: Scoring systems have been developed internationally based on lipid values and various combinations of clinical signs and cardiovascular history. The predictive value varies according to the test population, be it lipid clinic referrals, general population, or relatives of patients with FH. Also, there is increasing recognition of genetic heterogeneity in FH so that criteria are of differing predictive value depending on the genetic variant of FH. Summary: These clinical scoring systems are increasingly used to guide selection of patients for FH genetic testing but no single approach has yet emerged as the system of choice. Further refinement of these scoring tools using more sophisticated calculators are superseding the more manual approaches. These are well suited to web-based tools or smartphone applications

Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype

Background: Riboflavin (vitamin B2) is the precursor for FAD, the cofactor for methylenetetrahydrofolate reductase (MTHFR). MTHFR catalyzes the formation of 5-methyltetrahydrofolate, which acts as a methyl donor for homocysteine remethylation. Individuals with the MTHFR 677CT mutation have increased plasma total homocysteine (tHcy) concentrations, particularly in association with low folate status. It has been proposed that riboflavin may act together with folate to lower plasma tHcy, particularly in individuals with the thermolabile MTHFR T variant. Methods: We measured B-vitamin status and plasma tHcy in 126 healthy individuals 20–63 years of age (42 CC, 42 CT, and 42 TT MTHFR genotypes) at baseline and after three interventions (4 months): placebo plus natural diet; daily 400 µg folic acid supplement plus natural diet; and increased dietary folate to 400 µg/day. Results: At baseline and after nutritional intervention, lower riboflavin status was associated with increased plasma tHcy concentrations. Plasma tHcy was 2.6 µmol/L higher in the lowest plasma riboflavin quartile compared with the highest (P <0.02) and was 4.2 µmol/L higher in the highest erythrocyte glutathione reductase activation coefficient (EGRAC) quartile compared with the lowest (P <0.001). This effect was not restricted to those with the T allele. Folic acid given as a 400 µg/day supplement appeared to exacerbate a tendency toward riboflavin deficiency, as suggested by an increase in the proportion of individuals with EGRAC 1.4 from 52% to 65% after supplementation (P <0.05). Conclusions: Folate and riboflavin interact to lower plasma tHcy, possibly by maximizing the catalytic activity of MTHFR. The effect may be unrelated to MTHFR genotype

Web based tools to assess eligibility for genetic testing for Familial Hypercholesterolaemia (FH)

Selection of patients who are appropriate for genetic testing for FH is a balance between diagnostic yield and cost. The Wales FH service has implemented a clinical scoring system to guide the selection of patients based on lipid levels, personal and family history of cardiovascular disease plus physical signs. In an evaluation of 623 patients referred to lipid clinics, the proportion of patients with a mutation ranged from 4% in those scoring 5 or less to 85% in those scoring >15

Relationship between measurements of non-HDL-cholesterol and LDL-cholesterol in Familial Hypercholesterolaemia

Familial Hypercholesterolaemia (FH) is a monogenic disorder of Low Density Lipoprotein (LDL) metabolism which can be specifically diagnosed by genetic testing. However LDL-cholesterol (LDL-C) estimation has the drawback that it requires a fasting sample, because the Friedewald formula uses a factor relating to fasting triglyceride. Also other cholesterol containing lipoproteins are atherogenic and should be considered as part of cardiovascular risk assessment. Recent guidelines from National Institute for Health and Care Excellence (NICE) recommend non-HDL cholesterol (non HDL-C) for assessment of cardiovascular risk

Clinical experience of scoring criteria for Familial Hypercholesterolaemia (FH) genetic testing in Wales

Background/Objective Familial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The Wales FH service has developed scoring criteria to guide selection of patients for DNA testing, for those referred to clinics with hypercholesterolaemia. The criteria are based on a modification of the Dutch Lipid Clinic scoring criteria and utilise a combination of lipid values, physical signs, personal and family history of premature cardiovascular disease. They are intended to provide clinical guidance and enable resources to be targeted in a cost effective manner. Methods 623 patients who presented to lipid clinics across Wales had DNA testing following application of these criteria. Results The proportion of patients with a pathogenic mutation ranged from 4% in those scoring 5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest discriminatory factor. Scores gained from physical signs, family history, coronary heart disease, and triglycerides also showed a gradient in mutation pick-up rate according to the score. Conclusion These criteria provide a useful tool to guide selection of patients for DNA testing when applied by health professionals who have clinical experience of FH

Nutritional advice to increase soluble fibre intake does not change plasma folate or homocysteine in men with angina: a randomised controlled trial

Objective: To study the effect of advice to increase dietary soluble fibre, including fruit and vegetables, on plasma folate and homocysteine in men with angina. Design: Data were collected on a subset of subjects from the Diet and Angina Randomised Trial (DART II). In a randomised (2 × 2) factorial design, subjects received advice on either, neither or both interventions to: (1) increase soluble fibre intake to 8.0 g day−1 (fruit, vegetables and oats); (2) increase oily fish intake to 2 portions week−1. Those who received soluble fibre advice were compared with those who did not. Subjects were genotyped for C677T variant 5,10-methylenetetrahydrofolate reductase (MTHFR). Setting/subjects: Seven hundred and fifty-three male angina patients were recruited from general practice. Results: Plasma homocysteine concentrations were at the upper end of the normal range (median 11.5, 25% 9.4, 75% 14.0 μmol l−1). Baseline intake of fruit and vegetables was positively correlated with plasma folate (rs = 0.29, P < 0.01). Smokers had lower intakes of fruit and vegetables, lower plasma folate and higher homocysteine (all P < 0.01). Homozygotes for variant MTHFR had higher homocysteine concentrations at low plasma folate (P < 0.01). Reported intakes of fruit and vegetables and estimated dietary folate increased in the intervention group (ca. +75 g day−1, P < 0.01 and ca. +20 g day−1, P < 0.05, respectively). However, neither plasma folate (baseline/follow-up 4.5 vs. 4.4 μg l−1, P = 0.40) nor homocysteine (baseline/follow-up 11.7 vs. 11.7 μmol l−1, P = 0.31) changed. Conclusions: Plasma homocysteine, a cardiovascular risk factor, is influenced by MTHFR genotype, plasma folate and smoking status. Dietary advice successfully led to changes in fruit and vegetable intake, but not to changes in plasma folate or homocysteine, possibly because the fruits and vegetables that were chosen were not those richest in folate

A comparison of the effect of advice to eat either '5-a-day' fruit and vegetables or folic acid-fortified foods on plasma folate and homocysteine

Objective: To assess and compare the effects of natural folate (100 microg) with those of folic acid from fortified sources (100 microg/day) on plasma folate and homocysteine. Design: Randomized controlled trial (parallel groups). Setting: Men and women living in South Wales, UK. Subjects: A total of 135 healthy individuals recruited from the local workforce and blood donor sessions. All subjects possessed the 'wild-type' CC genotype for C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR). Interventions: Subjects underwent one of the following dietary interventions for 4 months: (1) fortified diet—usual diet plus 100 microg/day folic acid from fortified foods; (2) natural folate diet—usual diet plus 100 microg/day folate from natural sources; (3) control—usual diet. Results: The fortified group increased reported intake of folic acid from fortified foods compared to other groups (P<0.001) achieving an extra 98 microg/day (95% CI 88–108). The natural folate group increased reported intake of natural source folates compared with the other two groups (P<0.001), but achieved a mean increase of only 50 microg/day (95% CI 34–66). Plasma folate increased (P<0.01) by a similar amount in both intervention groups compared to controls (fortified group 2.97, 95% CI 0.8–5.1; natural group 2.76, 95% CI 0.6–4.9. Plasma homocysteine, vitamins B6 and B12 were not significantly changed. Conclusions: Subjects achieved increases in folate intake using fortified foods more easily than by folate-rich foods, however both sources increased plasma folate by a similar amount. These levels of intake were insufficient to reduce homocysteine concentrations in MTHFR CC homozygotes, but may be more effective in other genotypes. Sponsorship: This study was supported by the UK Ministry of Agriculture, Fisheries and Foods (latterly UK, Food Standards Agency, Project Reference N05002). The Kellogg Company of Great Britain provided funding for reimbursement of subjects for the cost of fortified foods

Lack of benefit of dietary advice to men with angina: results of a controlled trial

Objective: To see whether mortality among men with angina can be reduced by dietary advice. Design: A randomized controlled factorial trial. Setting: Male patients of general practitioners in south Wales. Subjects: A total of 3114 men under 70 y of age with angina. Interventions: Subjects were randomly allocated to four groups: (1) advised to eat two portions of oily fish each week, or to take three fish oil capsules daily; (2) advised to eat more fruit, vegetables and oats; (3) given both the above types of advice; and (4) given no specific dietary advice. Mortality was ascertained after 3–9 y. Results: Compliance was better with the fish advice than with the fruit advice. All-cause mortality was not reduced by either form of advice, and no other effects were attributable to fruit advice. Risk of cardiac death was higher among subjects advised to take oily fish than among those not so advised; the adjusted hazard ratio was 1.26 (95% confidence interval 1.00, 1.58; P=0.047), and even greater for sudden cardiac death (1.54; 95% CI 1.06, 2.23; P=0.025). The excess risk was largely located among the subgroup given fish oil capsules. There was no evidence that it was due to interactions with medication. Conclusion: Advice to eat more fruit was poorly complied with and had no detectable effect on mortality. Men advised to eat oily fish, and particularly those supplied with fish oil capsules, had a higher risk of cardiac death. This result is unexplained; it may arise from risk compensation or some other effect on patients' or doctors' behaviour. Sponsorship: British Heart Foundation, Seven Seas Limited, Novex Pharma Limited, The Fish Foundation

Methylenetetrahydrofolate reductase 677C-->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial

Background: Low folate status and elevated plasma homocysteine are associated with increased risk of neural tube defects and cardiovascular disease. Homocysteine responses to folate may be influenced by genetic variants in folate metabolism. Objective: We determined the effect of folate-enhancing dietary interventions on plasma folate and plasma total homocysteine (tHcy) with respect to the methylenetetrahydrofolate reductase 677C→T genotype. Design: A total of 126 healthy subjects (42 TT, 42 CT, and 42 CC genotypes) completed 3 dietary interventions (4 mo each) in random order: 1) exclusion diet (avoidance of folic acid–fortified foods and ingestion of a placebo daily), 2) folate-rich diet (increased intake of fortified and naturally folate-rich foods to achieve 400 μg folate/d), and 3) supplement (exclusion diet plus a folate supplement of 400 μg/d). Results: Plasma folate was higher (P ≤ 0.001) and plasma tHcy lower (P ≤ 0.001) after the folate-rich and supplement interventions than after the exclusion diet. Plasma folate was significantly greater after supplementation than after the folate-rich diet, but there was no significant difference in tHcy concentration (P = 0.72). TT homozygotes had higher plasma tHcy (14.5 compared with 8.9 μmol/L, P ≤ 0.001) and lower plasma folate (14.8 compared with 19.0 nmol/L, P ≤ 0.01) than did subjects with the CC genotype after the exclusion diet. CT heterozygotes had intermediate concentrations. The trend toward higher tHcy in TT homozygotes persisted throughout the study but was less marked with increasing folate intake (TT compared with CC after supplementation, P = 0.097). Conclusions: A folate-rich diet including folic acid–fortified foods or low-dose supplements effectively increases folate status. TT homozygotes require higher folate intakes than do individuals with the CT or CC genotype to achieve similar tHcy concentrations but are responsive to folate intervention