The influence of
glucocorticoids on lipid and
lipoprotein metabolism and atherosclerosis
Dr Ian Ross is a senior consultant endocrinologist attached to the Division of Endocrinology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa, and Groote Schuur Hospital, Cape Town. His major interests are Addison’s disease, glucocorticoids, clinical thyroidology and thyroid cancer. He received his PhD from UCT on the clinical aspects of Addison’s disease. Prof. David Marais specialised in internal medicine, then received a Medical Research Council scholarship to study lipoprotein metabolism in medical biochemistry before resuming a consultant post in internal medicine at Groote Schuur Hospital. He joined the lipid clinic in 1984 and developed a diagnostic and research laboratory for dyslipidaemias. He headed the clinic from 1990 to 2012, when he joined the Department of Chemical Pathology, National Health Laboratory Service and Faculty of Health Sciences, UCT. He is also a member of the MRC Cape Heart Group.
Glucocorticoids have multiple therapeutic uses, but their impact on lipid metabolism and cardiovascular disease risk is not always considered during long-term treatment. Genetic variations, environmental factors and the reasons for glucocorticoid treatment all influence the lipid profile and atherosclerosis. Responses to glucocorticoid treatment may therefore be variable and unpredictable. Despite the frequency with which pharmacological doses of glucocorticoids are used, surprisingly few publications examine their effects on lipid metabolism and atherosclerosis. Patients managed with glucocorticoids should have their cardiovascular risk assessed, especially if long-term treatment is planned. While some apparent favourable changes have been reported in high-density lipoprotein metabolism, very-low-density lipoprotein and low-density lipoprotein responses seem unfavourable. The impact of glucocorticoids on atherosclerosis, which is often viewed as an inflammatory process, is unclear. Glucocorticoid treatment should be undertaken for appropriate indications, but in some instances special attention should be given to management of dyslipidaemia, as long-term survivors of treatment are likely to encounter atherosclerosis.
S Afr Med J 2014;104(10):671-674.
Lipoproteins transport lipids in the circulation in four major pathways: (i) a postprandial (exogenous) pathway for chylomicrons; (ii) an endogenous pathway involving very-low-density lipoprotein (VLDL) for triglyceride (TG) transport from the liver; (iii) a low-density lipoprotein (LDL) pathway from a proportion of VLDL as a source of cholesterol for cells; and (iv) a reverse cholesterol transport pathway by high-density lipoprotein (HDL).1 These pathways and the reported effects of glucocorticoids are shown in Fig. 1.
Fig. 1. Schematic view of lipoprotein metabolism including the effects of glucocorticoids. Adapted with permission from Marais. (ABCA1 = adenosine binding cassette transporter A1; apoE = apolipoprotein E; Ai = apolipoprotein Ai; BA = bile acid; B100 = apolipoprotein B100; C = cholesterol; CE = cholesteryl ester; CETP = cholesterylester transfer protein; CM = chylomicron; Cii = apolipoprotein Cii; FA = fatty acids; HDL2 = high-density lipoprotein 2; HDL3 = high-density lipoprotein 3; HL = hepatic lipase; TG = triglyceride; LDL = low-density lipoprotein; LDLR = LDL receptor protein; LPL = lipoprotein lipase; LRP = low-density lipoprotein receptor protein; LCAT = lecithin cholesterol acyltransferase; SRB1 = scavenger receptor B1; VLDL = very-low-density lipoprotein.)
Exogenous TG pathway
Chylomicrons, comprising 85 - 90% TG and containing
apolipoprotein B (apo B)-48 (apoB48), apolipoprotein Ai (apoAi)
and apolipoprotein Aiv (apoAiv), are produced in enterocytes,
traverse the thoracic duct and ultimately reach the systemic
circulation. Lipoprotein lipase anchored on cells by heparan
sulphate proteoglycans hydrolyses TG at the vascular
endothelium, yielding non-esterified fatty acids (NEFAs) and
remnants, proportionately richer in cholesterol esters.
Chylomicron remnants are rapidly cleared by liver remnant
as a result of apolipoprotein E (apoE) acquired in the
circulation. Dietary fat restriction will have a significant
impact on severe hypertriglyceridaemia.
Endogenous TG pathway
VLDL is assembled on apolipoprotein B-100 (apoB100) and
comprises 50% TG, 20% cholesterol esters, 15% phospholipids and
15% protein. Secretion is enhanced by increasing delivery of
NEFAs from adipose tissue during starvation or in diabetes.3 VLDL is
also hydrolysed by lipoprotein lipase. These remnants and other
small lipoproteins (LDL and HDL) can undergo hydrolysis of TG by
hepatic lipase, forming progressively smaller particles. VLDL
remnants are proportionately richer in cholesterol, and some
The release of fatty acids from adipose tissue and their uptake
in the liver will enhance VLDL production and may cause
LDL contains the majority of cholesterol in the plasma. Its
mass comprises 35% cholesteryl ester, 10% unesterified
cholesterol (UC), 10% TG and 20% phospholipids. ApoB100 almost
entirely accounts for the 25% of protein. Most circulating LDL
is taken up by hepatocyte LDL receptors. Increased VLDL could
increase LDLC while also resulting in modulation of particle
size. This process requires cholesterylester transfer protein
(CETP) to enrich with TG, after which hepatic lipase hydrolyses
the TG. The plasma LDL concentration may also be raised by
decreased clearance (by LDL receptors) in familial
Reverse cholesterol transport
HDL is the smallest of the lipoproteins. About half is lipids (25% phospholipids and 15% cholesterylester, while UC and TG both constitute 5%). The remainder is chiefly apoAi and apolipoprotein Aii (apoAii). The liver and intestine secrete apoAi that may initiate particle formation, which may also result from lipolysis of TG-rich lipoproteins4 when apoAi and the relative excess of phospholipids pinch off from the lipoprotein. Lecithin-cholesterol acyltransferase (LCAT) esterifies UC, using long-chain fatty acids from phospholipids. Cholesteryl esters migrate to the core, forming more mature spherical particles (HDL3) and later larger and less dense HDL. CETP transfers cholesteryl ester from HDL2 to TG-rich lipoproteins, permitting delivery of cholesterol to the liver, and in exchange HDL receives TG.4 Hepatic lipase hydrolyses TG, regenerating smaller HDL3 particles. Exchange of TG into LDL similarly produces smaller particles. In HDL, esterification of UC permits more UC to be accepted from cells or other lipoproteins. HDL delivers cholesterol directly to the liver, leading to its excretion in bile.5
Lipid and lipoprotein changes with corticosteroids
Dyslipidaemia, hyperglycaemia and hypertension are the most significant cardiovascular adverse effects resulting from glucocorticoid therapy,6 but mechanistic insights are incomplete. Documented changes in human lipid profiles on varying doses of prednisone7-10 include elevated VLDL, TG and LDL cholesterol, and either increased or decreased HDL cholesterol.
Animal studies of lipid changes in steroid use
Hydrocortisone (single dose) administered to rabbits with
atherosclerosis raised TG but not total cholesterol (TC),11
suggesting increased VLDL production or possibly decreased
metabolism. In rats, dexamethasone and triamcinolone (but not
hydrocortisone) increased plasma TC and TG.12
Hydrocortisone administered to rats at 100 µg/g of body mass
reduced TC. Hydrocortisone, triamcinolone and dexamethasone
increased apoAi, with the greatest increases documented for
triamcinolone and dexamethasone. Dexamethasone raised apoAiv
the most, and triamcinolone caused the greatest increase in
apoE, yet reductions in apoE levels occurred in rats receiving
administered to normal rats for 8 days increased TG and
almost doubled TC,13 probably owing to a
reduction in lipoprotein lipase activity and decreased HDL
cholesterol.14 ApoE decreased with
hydrocortisone, either as a result of less hepatic secretion
or increased catabolism of apoE-containing lipoproteins, but
lower production of apoE by extrahepatic tissues has also
been proposed.15 The brain, spleen and
kidney produce apoE, aiding redistribution of cholesterol from
cells with an excess of cholesterol to those requiring it.15
ApoAi increased with most glucocorticoids, but especially with
triamcinolone and dexamethasone, resulting in increased HDL
15 Hepatic apoAi mRNA
increased in cultured rat hepatocytes exposed to
down-regulation of LDL receptors in rats followed
methylprednisolone administration, accounting for elevated
LDL and TC.17 Overall, animal
models illustrate marked effects on HDL and some adverse
effects on LDL, as well as differences between the drugs.
Human studies with glucocorticoids
The impact of glucocorticoid hormones on lipoprotein metabolism can be examined in normal variation, acute and chronic dosing, replacement therapy, and hypercortisolism. Positive correlations exist between LDL cholesterol and endogenous plasma cortisol in healthy men aged between 52 years and 67 years.18 Glucocorticoids alter plasma lipids within 14 days.10 Acute effects of 3 mg dexamethasone (twice daily simulating acute stress) in young men included lower highly sensitive C-reactive protein levels and increased HDL cholesterol; LDL cholesterol, NEFA and TG were not altered.19 Glucocorticoids reduce hepatic lipase and CETP, resulting in elevated HDL cholesterol after cardiac transplantation.20 In the third National Health and Nutrition Examination Survey, glucocorticoid use was associated with higher HDL and lower TC/HDL cholesterol ratios.21 Both glucocorticoid use and endogenous hypercortisolism (Cushing’s disease) resulted in elevated TC and LDL cholesterol. Glucocorticoid replacement in hypopituitary patients lowered VLDL, LDL cholesterol, LCAT and CETP.
Based on animal and human studies, exposure to glucocorticoids
may produce either increased or decreased HDL cholesterol.
Changes in reverse cholesterol transport or other effects may
modulate atherosclerosis. Some studies corroborate up-regulated
hepatic LDL receptor activity, explaining a decrease in LDL
cholesterol. While glucocorticoids are known to have pleiotropic
actions on physiological and pathological processes, lipoprotein
responses and homoeostasis are varied, but are potentially
atherogenic (Table 1).
Hypercortisolism stimulates the production of VLDL.6 Subclinical Cushing’s syndrome has been associated with dyslipidaemia. Rheumatoid arthritis sufferers frequently have high TC and LDL cholesterol and decreased HDL cholesterol. Untreated rheumatoid arthritis patients may have lower HDL cholesterol levels relating to inflammation and acute-phase response. Treatment with glucocorticoids may dampen inflammation favourably, though this may not apply to atherogenesis.7 A meta-analysis found an increase of cardiovascular and cerebrovascular disease by 59% and 50%, respectively, compared with the general population. Accelerated atherosclerosis in systemic lupus erythematosus has been attributed to the disease or to glucocorticoid therapy.
Hypopituitary patients on replacement therapy
(hydrocortisone, thyroxine and sex steroids) are subject to
increased morbidity and mortality from accelerated
atherosclerosis. Optimally replaced patients had adverse lipid
profiles, with increased TG, TC and LDL cholesterol compared
with controls. Daily hydrocortisone supplementation of less
than 20 mg/d in growth hormone-replaced patients had the least
Clinical approach to glucocorticoid treatment
Doctors considering glucocorticoid treatment in patients with chronic disorders should be aware that cardiovascular risk may increase. Chronic inflammatory conditions can predispose to vascular disease, and treatment may aggravate risk through dyslipoproteinaemia or other mechanisms. Until further studies inform otherwise, prevailing guidelines should be followed. Risk calculations based on clinical parameters and lipid profiles as suggested guidelines offer the best guidance on the threshold for treatment, but may not be accurate. The premorbid lipid profile as well as levels during the illness may guide management. Exercise and dietary recommendations should be the norm.
Detailed clinical assessments of a personal and family history of premature cardiovascular disease, physical signs and lipoprotein profiles will assist in the diagnoses listed in Table 2. Physical signs are not invariably present. Certain recessive disorders, e.g. dysbetalipoproteinaemia in subjects homozygous for apolipoprotein E2 (apoE2), manifest only when metabolic stress occurs. Partial lipoprotein lipase activity in heterozygotes may predispose to hypertriglyceridaemia. It is expected that glucocorticoid therapy will have a small impact on the lipoprotein profile in patients with normal genetic constitutions, while benefiting the chronic inflammatory condition. Occasionally, severe dyslipidaemia may be precipitated by glucocorticoid treatment, and in this setting special treatment with statins will be required for LDL hypercholesterolaemia, or fibrates for severe hypertriglyceridaemia. Successful treatment of the nephrotic syndrome with glucocorticoids will result in improved lipid profiles. Precipitation of diabetes by glucocorticoid therapy can affect the lipid profile and cardiovascular risk. Hypertension will similarly require a re-evaluation of risk and preventive actions to combat cardiovascular disease.
Treatment of conditions requiring glucocorticoids together with disease-modifying agents is likely to prolong life expectancy and therefore raise the risk of cardiovascular disease. This risk is related at least in part to lipoprotein responses, as summarised in this article. More studies are required to evaluate cardiovascular risk in replacement and anti-inflammatory treatment, as well as the effects of different doses and forms of corticosteroid.
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Accepted 30 April 2014.
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