A place for assaying serum apolipoprotein AI and B?

Soran et al. ¹ report in this issue that apolipoprotein B100 (apoB) appears better than calculated low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) as a target for statin treatment. They also suggest that serum apoB offers a more consistent treatment target which is independent of hypertriglyceridaemia.

Apolipoproteins are thoroughly reviewed by Dominiczak and Caslake ² also in this current issue. ApoB is predominantly found with LDL particles but also with intermediate-density lipoprotein and very low-density lipoprotein (VLDL). It is the ligand for the LDL receptor and apoB-containing lipoproteins are associated with atherogenesis. LDL has one molecule of apoB per particle, although its cholesterol and triglyceride content can vary. ApoB100 and apoB48 (involved in the clearance of lipoproteins such as chylomicrons postprandially) are encoded by the same gene and the resultant translated proteins are the product of tissue-specific RNA editing. ApoAI, and to a lesser extent, apoAII, are the predominant apolipoproteins of HDL-particles which manifest anti-inflammatory and antioxidant activities. ApoAI also acts as a co-factor for lecithin cholesterol acyl-transferase (LCAT) and the ATP-binding cassette (ABC) protein, ABCA1, and thus is involved in reverse cholesterol transport.

Sniderman et al. ³ reported higher serum apoB concentrations in hypertriglyceridaemic patients than would be predicted from LDL-C concentration alone and named this condition hyperapobetalipoproteinaemia, which is associated with cardiovascular disease. As Sniderman quotes ‘the underestimate of atherogenic particle number by LDL-C when small dense cholesterol-depleted LDL particles predominate is the biological reason as to why apoB outperforms LDL-C as a marker of risk and a measure of the adequacy of LDL-lowering therapy’. ⁴ In other words, although its cholesterol content will vary depending on the stage of modification of that lipoprotein during its sojourn in the circulation, there is only one apoB molecule per LDL particle. In the presence of hypertriglyceridaemia, a reduced serum apoB concentration suggests a high VLDL concentration and low numbers of remnant and LDL particles and thus a reduced likelihood of atherosclerosis.

The serum apoB:apoAI ratio has been shown to be strongly related to enhanced risk of myocardial infarction and stroke in the Apolipoprotein-related MOrtality RISk study (AMORIS). ⁵ The INTERHEART study ⁶ also reported that the serum apoB:apoAI ratio may be a more useful measure of cardiovascular risk than either the apoB or apoAI measure alone or serum LDL-C. Similarly, the Quebec Cardiovascular study ⁷ showed that the greatest cardiovascular risk was associated with elevated serum apoB and reduced LDL particle size. Furthermore, various other studies have suggested that the concentration of the atherogenic lipoprotein particles measured by apoB is more predictive of cardiovascular risk than serum LDL-C and non-HDL-C. ^8–11 In a variety of statin intervention studies, ^12–14 plasma apoB concentration was more predictive of cardiovascular outcome than the LDL-C, thus supporting the findings of Soran et al. ¹

Usefully, measurement of apolipoproteins can be performed in non-fasting samples, and high triglyceride concentrations which can interfere with some direct measures of HDL-C and LDL-C may have less effect upon the assay of serum apoAI and apoB. ^3,4 It has also been proposed that serum apoB measurement may be preferable to the ‘lipid profile’ for monitoring patients with lipoprotein disorders, although this might be problematic in patients where serum triglyceride concentrations fluctuate. ¹⁵

Serum apoB concentrations are usually increased in familial hypercholesterolaemia, familial defective apoB (FDB), hyper Lp(a) syndrome and polygenic hypercholesterolaemia. In hyperapobetalipoproteinaemia, serum apoB is high in the presence of ‘normal’ total cholesterol concentration, while in familial hypertriglyceridaemia, serum apoB concentrations are usually ‘normal’ which can help distinguish it from familial combined hyperlipidaemia (FCH). The diagnostic criteria sometimes used for FCH are as follows: a serum cholesterol >95th centile; serum triglyceride >90th centile; serum apoB>1.25 g/L with a family history of hyperlipidaemia in a first-degree relative. ApoB is abnormal in FDB where there is usually a mutation in the apoB gene resulting in a substitution of arginine at the 3500 amino-acid position for glutamine. ¹⁶

Serum apoB concentration is low in abetalipoproteinaemia where there is impaired chylomicron and VLDL synthesis and failure of lipid transport from the liver and intestine usually due to a defect in microsomal triglyceride transfer protein. Clinical features may consist of abnormal transport of fat-soluble vitamins, steatorrhoea, progressive ataxia, retinitis pigmentosa and acanthocytosis. In hypobetalipoproteinaemia, usually a less severe syndrome occurs, sometimes due to a truncated form of apoB. Hypobetalipoproteinemia usually shows less than the 5th centile of serum total cholesterol or LDL-C concentrations and a total serum apoB of less than 0.5 g/L. ¹⁷

There are rare disorders of apoA metabolism such as hyperalphalipoproteinaemia where there is both high serum HDL-C and apoAI, and conversely low serum HDL-C and reduced apoAI occur in Tangier's disease, LCAT deficiency, fish-eye disease, familial hypoalphalipoproteinaemia and also various apoAI deficiency and mutation conditions; some of these being associated with premature cardiovascular disease. ¹⁸

It has been argued that standardization of serum apoAI and apoB assay is more robust than that of LDL-C and HDL-C, in part, due to the availability of suitable reference materials and uniformity of methodologies. Dominiczak and Caslake ² point out that the assays for serum apoAI and apoB are generally well standardized, with immunoturbidimetry or nephelometry probably most commonly used, although immunoradiometric, immunoelectrophoresis and immunochemical methods are also possible. ¹⁹ Dominiczak and Caslake ² also quote that using reference material SP-07, the between-laboratory coefficient of variation (CV) for apoAI was 2.1–5.6% and for apoB 3.1–6.7%. They remind us that the precision of currently available apolipoprotein measurements is usually less than 5%, although this varies between laboratories with external quality assessment schemes disappointingly showing higher CVs of up to 10%.

Are we likely to see serum apoAI and B assays used in the next few years in routine clinical practice in the UK? I think this is doubtful. Although the science is generally sound and the trial data convincing to support the use of the serum apoAI:apoB ratio as a marker of cardiovascular risk, as Faergeman ²⁰ pragmatically states ‘it is naive to contemplate educating the world's public in apolipoproteinology’. It has taken years for serum LDL-C and HDL-C to be accepted in cardiovascular risk assessment and in a financially restrained health-care system, perceived ‘new’ tests such as assay of serum apoAI or B are unlikely to be rapidly incorporated in routine clinical practice. More likely is to see the serum apoB:apoAI ratio used by specialists such as lipidologists and metabolic physicians, to further explore cardiovascular risk assessment in certain patient groups and also the use of individual serum apoAI and apoB assays to help diagnose lipid abnormalities such as hypoalphalipoproteinaemia and apoAI deficiency, as well as FCH and hypobetalipoproteinaemia, respectively.

DECLARATIONS

Competing interests: None.

Funding: None.

Ethical approval: Not required.

Guarantor: MAC.

Contributorship: MAC is the sole author.