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Lipid and lipoprotein disorders 

Lipid and lipoprotein disorders

Lipid and lipoprotein disorders

P.N. Durrington



Modifications to take account of increased knowledge of lipoprotein pathophysiology and the areas of agreement and disagreement between the recommendations for treatment in the USA and Europe.

Updated on 28 Nov 2013. The previous version of this content can be found here.
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date: 30 March 2017

Lipid physiology

Lipids are a heterogeneous group of substances that are distinguished by their low solubility in water and their high solubility in nonpolar (organic) solvents. They are essential as energy stores and respiratory substrates, as structural components of cells, as vitamins, as hormones, for the protection of internal organs, for heat conservation, for digestion, and for lactation.

The main forms of lipid are (1) triglycerides—formed by the esterification of glycerol with fatty acids; provide the body’s principal energy store (a 70-kg man contains some 15 kg of stored triglycerides, representing 135 000 kcal of energy); (2) phospholipids—these have at least one fatty acyl group esterified to an alcohol and one phosphate group linked both to the alcohol and to another organic compound; essential components of cell membranes; (3) cholesterol—an essential component of cell membranes; a precursor for the synthesis of steroid hormones, vitamin D, and bile acids.

Lipoproteins—these are macromolecular complexes of lipid and protein: their principal function is to transport lipids through the vascular and extravascular body fluids, and they are also found as components of milk. Their protein components include apolipoproteins and enzymes.

Transport of lipids from the gut to the liver and tissues—this occurs as follows: (1) the products of fat digestion are esterified in the enterocyte, combined with apolipoprotein (apo) B48, and secreted into the lymph (chyle) as chylomicrons; (2) after entry into the blood circulation chylomicrons that have acquired apoC-II (from high-density lipoprotein, HDL) activate lipoprotein lipase, which hydrolyses triglycerides components of which are taken up locally in tissues expressing this lipase; (3) with removal of triglycerides the circulating chylomicrons become smaller and relatively richer in cholesterol and protein; (4) these chylomicron remnants are largely removed from the circulation by the liver, mainly via the ‘remnant receptor’.

Transport of lipids and cholesterol from the liver to the tissues—this is important in the fasting state and mainly occurs as follows: (1) the liver secretes a triglyceride-rich lipoprotein known as very low-density lipoprotein (VLDL); (2) these are processed in a similar manner to chylomicrons, with acquisition of apolipoproteins and removal of triglycerides by lipoprotein lipase; but also (3) free cholesterol within VLDL is esterified by a mechanism that involves transfer to high density lipoprotein (HDL) and back to VLDL; and (4) most VLDL is converted to smaller low-density lipoprotein (LDL) particles through the intermediary of intermediate density lipoprotein (IDL); (5) LDL particles deliver cholesterol to the tissues through LDL receptors.

‘Reverse cholesterol transport’—cholesterol is exported by the gut and liver in quantities which greatly exceed its peripheral catabolism; it gets back from the tissues to the liver via HDL.

Disorders produced by raised concentrations of lipoproteins

The exponential relationship between cholesterol and cardiovascular mortality and morbidity depends on the LDL present. However, except at particularly high levels the risk conferred by LDL is determined by whether or not it is combined with other risk factors (smoking, hypertension, diabetes etc.). Hence cholesterol levels must generally be viewed in the context of an individual’s overall risk.

Cardiovascular morbidity and mortality—depending on the LDL cholesterol and its involvement in atherogenesis, there is an exponential relationship between serum cholesterol and the incidence of coronary heart disease within populations. However, the risk conferred by a particular level of cholesterol depends on whether or not it is combined with other risk factors (smoking, hypertension, diabetes, etc.), hence no cholesterol level can be specified which demands a particular therapeutic response: it must always be viewed in the context of an individual’s overall cardiovascular risk.

Acute pancreatitis—increase in triglyceride-rich lipoproteins without any increase in LDL is only a modest risk factor for atheroma, but there is an increased likelihood of acute pancreatitis in all types of severe hypertriglyceridaemia.

Particular lipid and lipoprotein disorders

Polygenic hypercholesterolaemia—most hypercholesterolaemia (cholesterol >5 mmol/litre, i.e. 200 mg/dl]) is not due to a single cause, but to some combination of dietary fat, obesity, and individual susceptibility to develop hypercholesterolaemia in the presence of acquired factors such as obesity or a diet high in saturated fat due to overproduction of VLDL by the liver for unknown reasons.

Monogenic familial hypercholesterolaemia—this is dominantly inherited, leads to serum cholesterol concentrations of typically 9 to 11 mmol/litre (350–450 mg/dl), and is due to mutations in the LDL receptor gene. Heterozygotes often have tendon xanthomata, xanthelasmata, corneal arcus at a young age, and premature coronary disease.

Hypercholesterolaemia combined with hypertriglyceridaemia—primary hyperlipoproteinaemia of this type is most commonly due to a polygenic tendency exacerbated by acquired nutritional factors, such as obesity. A rare, severe phenotype can also be caused by decreased clearance of chylomicron remnants and IDL (collectively β‎-VLDL) at the hepatic ‘remnant’ (apoE) receptor, when striate palmar xanthomata and tuberoeruptive xanthomata are often seen. Cardiovascular risk is greater for any given level of cholesterol when the serum triglyceride concentration is also elevated.

Severe hypertriglyceridaemia—severe hypertriglyceridaemia ensues when increased hepatic VLDL production, for example due to alcohol excess or diabetes, is associated with decreased triglyceride clearance. Familial lipoprotein lipase deficiency is a rare cause. Eruptive xanthomata are characteristic. Acute pancreatitis may occur when serum triglyceride levels exceed 20 to 30 mmol/litre (2000–3000 mg/dl).

Secondary hyperlipoproteinaemias—these can be caused by diabetes mellitus, obesity, hypothyroidism, chronic kidney disease, drugs, and liver disease.

Management of hyperlipoproteinaemia

Decision to treat—this is not based simply on any particular lipid or lipoprotein value, but on an assessment of individual risk. It is generally agreed that dietary advice to reduce obesity by a decrease in dietary energy intake and to decrease saturated fat consumption is appropriate for all people with LDL cholesterol >2.0 mmol/litre (80 mg/dl), which includes most adults living in the developed world.

Drug treatment—this is justified generally in established atherosclerotic cardiovascular disease, familial hypercholesterolaemia and other severe, monogenic hyperlipoproteinaemias and in diabetes (certainly after the age or forty years and sometimes younger). In other patients cardiovascular risk high enough to warrant statin treatment, (often defined as >20% over 10 years), can be calculated for an individual patient by reference to standard algorithms or charts. The first-line therapy in all forms of hypercholesterolaemia, except that associated with triglyceride levels above 11 mmol/litre (1000 mg/dl), are the statin drugs (3-hydroxy-3-methylglutaryl CoA reductase inhibitors). These should generally be initiated if LDL cholesterol is more than 2.0 mmol/litre (80 mg/dl), with the aim to decrease LDL cholesterol to below this value or by 30%, whichever is the lowest. Other drugs used to reduce cholesterol include bile acid sequestrating agents and ezetimibe (a cholesterol absorption inhibitor). Fibrate drugs may be of value in patients whose hypercholesterolaemia is combined with marked hypertriglyceridaemia.

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