Lipid disorders

Lipids from

Lipids from

Fig. 25.1 Pathways of lipid transport. Adapted from Knopp R H 1999 New England Journal of Medicine 341:498-51 I (with permission).

This chapter addresses approaches, non-drug as well as drug, to correct abnormal lipid profiles and diminish vascular disease and its consequences.

Deposition of cholesterol in the arterial wall is central to the atherosclerotic process. Carriage of VLDL, remnant lipoprotein, and LDL to arteries can thus be viewed as potentially atherogenic. In the reverse process, HDL carries cholesterol away from the arterial wall and can be regarded as protective against atherogenesis. Overproduction of VLDL in the liver raises plasma VLDL, remnant lipoprotein and LDL if the capacity to metabolise these lipoproteins is compromised either by a primary (inherited) and/or secondary (environmental) abnormality.

Elevation of LDL-cholesterol is associated particularly with risk of coronary heart disease risk, but it is increasingly clear that moderately raised triglycerides or VLDL or remnants in the presence of low HDL-cholesterol may also be atherogenic.

There are five primary inherited lipoprotein disorders which disturb lipid matabolism at the points indicated in Figure 25.1. These are:

• Familial hypertriglyceridemia (FHTG)

(uncommon), including lipoprotein lipase (LPL) deficiency, in which low LPL activity results in decreased removal, and thus increase of serum triglyceride; there is increased hepatic secretion and thus raised plasma concentration of triglyceride-rich VLDL. Patients are at risk of recurrent acute pancreatitis when plasma triglycerides exceed 10 mmol/1, and especially 20 mmol/1.

• Familial combined hyperlipidemia (FCHL) (common and most important) in which there is increased hepatic secretion of apolipoprotein B containing VLDL, and conversion to LDL; in consequence plasma LDL and VLDL are raised. Patients exhibit macrovascular disease (coronary heart, peripheral and cerebral).

• Remnant removal disease (RRD, also called remnant lipaemia, familial dysbetalipoproteinemia) (uncommon) in which there is a defect of apolipoprotein E. This is the major ligand that allows internalisation and subsequent metabolism of remnant particles derived from VLDL and chylomicrons. The consequence is accumulation of VLDL remnants called intermediate density lipoprotein (IDL) with cholesterol and triglycerides usually in the range 6-9 mmol/1. Patients experience severe macrovascular disease (as above).

• Familial hypoalphalipoproteinemia (rare) in which the serum concentration of (protective) HDL is low. Coronary heart and peripheral vascular disease result.

• Familial hypercholesterolemia (FH) (common) is characterised by elevation of total and LDL-cholesterol in plasma. In the more severe heterozygous form, this affects about 1:500 of the population (one copy of the LDL-receptor protein is absent or defective). LDL-cholesterol is elevated from childhood. Untreated, half the males will be dead by 60 years, females 10 years later. The principal consequence is coronary heart, but occasionally also peripheral and cerebrovascular disease.

Most commonly, patients present with raised total and LDL-cholesterol of lesser degree which results from overproduction of VLDL in the liver due to a combination of high dietary fat, obesity and individual (inherited) susceptibility; it is thus called polygenic, is manifest in adult life, with atherosclerosis occuring early but not as early as with FH.

Secondary hyperlipidaemias results from: liver and biliary disease, obesity, hypothyroidism, diabetes, diet, alcohol excess, renal disease (nephrotic syndrome) and drugs (including etretinate, HIV protease inhibitors, thiazide diuretics, oral contraceptive steroids, glucorticosteroids, ^-adrenoceptor antagonists, ciclosporin).

The most severe hyperlipidaemias usually occur in patients with concurrent conditions, e.g. diabetes mellitus with one of the primary hyperlipidaemias.

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