Hyperlipidaemias
All cells require lipids
(fats) to synthesize membranes and provide energy. Lipids are transported
in the blood as lipoproteins. These small particles consist of a core of
triglycerides and cholesteryl esters, surrounded by a coat of phospholipids,
cholesterol and proteins termed apolipoproteins or apoproteins.
Apoproteins stabilize the lipoprotein particles and help target specific types
of lipoproteins to various tissues. Hyperlipidaemias are abnormalities
of lipoprotein levels which promote the development of atherosclerosis (see
Chapter 37) and coronary heart disease (CHD; see Chapters 40–42).
Figure 36 illustrates pathways of lipid transport in the
body. The exogenous pathway (left side of Figure 36) delivers ingested
lipids to the body tissues and liver. Ingested triglycerides and cholesterol
are transported by the protein Niemann–Pick C1-like 1 (NPC1L1) into the mucosal
cells lining the intestinal lumen, which combine them with apoprotein apo
B-48, forming nascent chylomicrons which are secreted into the
lymph, pass into the bloodstream, and combine with apo E and apo C-II to become
chylomicrons. These bind to the capillary endothelium in muscle and
adipose tissue, where apo CII activates the endothelium-bound enzyme lipoprotein
lipase (LPL)
which hydrolyses the triglycerides to fatty acids which
enter the tissues. The liver takes up the residual chylomicron remnants.
These are broken down to yield cholesterol, which the liver also synthesizes.
The rate-limiting enzyme in hepatic cholesterol synthesis is hydroxy-methylglutaryl
coenzyme A reductase (HMG-CoA reductase). The liver uses cholesterol to
make bile acids. These pass into the intestine and act to solubilize
dietary cholesterol so it can be absorbed via NPC1L1. Bile acids are almost
entirely reabsorbed and returned to the liver, although about 0.5 g/day is lost
in the faeces, providing a path by which the body excretes cholesterol.
The endogenous pathway cycles lipids between the
liver and peripheral tissues. The liver forms and secretes nascent very low
density lipoproteins (VLDLs), consisting mainly of triglycerides with some
cholesterol and apo B-100, into the lacteal vessels. These acquire apo E and
apo C-II from HDL in the plasma to become VLDL. As with chylomicrons, apo C-II
activates LPL causing VLDL triglyceride hydrolysis and provision of fatty acids
to body tissues. As it is progressively drained of triglycerides, VLDL becomes intermediate
density lipoprotein (IDL) and then low-density lipoprotein (LDL),
losing all of its apoproteins (to HDL) except for apo B-100 in the
process. Most of the LDL, which contains mainly cholesteryl esters (CE), is
taken up by the liver; the rest serves to distribute cholesterol to the peripheral tissues.
Cells regulate their cholesterol uptake by expressing more LDL receptors (which
bind to apo B-100) when their cholesterol requirement increases.
Cholesterol is removed from tissues by high-density
lipoprotein (HDL). HDL is initially assembled in the plasma from lipids and
apoproteins (mainly apo A1, but also apo C-II and apo E) lost by other
lipoproteins, and then progressively accumulates cholesterol (which it stores
as CE) from body tissues. Cholesteryl ester transfer protein (CETP),
which is in the plasma, transfers these from HDL to VLDL, IDL and LDL, which
return them to the liver. This process by which HDL transports cholesterol to
the liver from the rest of the body is termed reverse cholesterol transport,
and probably explains why plasma HDL levels are inversely proportional to the
risk of developing CHD.
Hyperlipidaemias:
types and treatments Primary hyperlipidaemias are
caused by genetic abnormalities affecting apoproteins, apoprotein receptors or
enzymes involved in lipoprotein metabolism, and occur in about 1 in 500 people.
Secondary hyperlipidaemias are caused by conditions or drugs (e.g.
diabetes, renal disease, alcohol abuse, thiazide diuretics) affecting
lipoprotein metabolism. However, hypercholesterolaemia is most commonly caused
by consumption of a diet high in saturated fats, probably because
this decreases hepatic lipoprotein clearance. Although hyperlipidaemia often
involves simply an excess of LDL cholesterol (LDL-C), many people, especially
those with metabolic syndrome (see Chapter 34) have a combination of
high LDL-C, high triglycerides (high VLDL), and low HDL cholesterol (HDL- C) levels in
their plasma. This pattern is thought to confer a particularly large risk of
developing CHD.
The treatment of hyperlipidaemias aims to slow or reverse
the progression of atherosclerotic lesions by lowering LDL-C and/or
triglycerides and to raise HDL-C. Current US guidelines state that LDL-C should
be <160 mg/dL (4.1 mmol/L) for those who are otherwise at low risk of
developing CHD, whereas for high-risk patients with existing CHD, diabetes or a 10-year
risk of developing CHD of >20%, LDL-C should be <100 mg/dL (2.6 mmol/L),
and ideally less than 70 mg/dL (1.8 mmol/L).
Treatment often begins with a low fat, high carbohydrate
diet. If this fails to normalize hyperlipidaemia adequately after 3 months,
therapy with a lipid-lowering drug is considered. The vast majority of those
with high LDL-C receive ‘statins’, which have been consistently shown to reduce
CHD and the mortality it causes. Those with high triglycerides and low HDL-C
are also often given ‘fibrates’ or niacin (each used by ∼10% of patients).
HMG-CoA reductase inhibitors or ‘statins’ include simvastatin, lovastatin, pravastatin,
fluvastatin, mevastatin, atorvastatin and rosuvastatin. The landmark
Scandinavian Simvastatin Survival Study (4S) reported in 1994 that
treatment with simvastatin of CHD patients with high LDL-C reduced
cardiovascular mortality by 42% over a 6-year period. Statins act by reducing
hepatic synthesis of cholesterol, causing an upregulation of hepatic receptors
for B and E apoproteins. This increases the clearance of LDL, IDL and VLDL from
the plasma. Statins also modestly increase plasma HDL-C levels by an unknown
mechanism. Although the main benefits of statins result from their
lipid-lowering effects, they also probably reduce CHD through additional mechanisms.
These include an enhancement of nitric oxide release, possibly due to activation of
the PI3K–Akt pathway (see Chapter 24), and also anti-inflammatory and
antithrombotic effects. Some of these effects occur because the inhibition of
HMG-CoA reduces cellular concentrations of lipids required for the functioning
of the monomeric G proteins Rho (Rho acts to suppress eNOS expression) and Ras (Ras
stimulates NFκB, which is involved in the expression of many pro-inflammatory
genes). Serious statin-associated adverse effects are rare. They include
hepatoxicity and rhabdomyolysis (destruction of skeletal muscle), the risk of
which is increased with concomitant use of nicotinic acid or a fibric acid
derivative.
Both niacin (nicotinic acid) and fibrates
(fibric acid derivatives) are mainly used in patients who are receiving
statins but whose triglyceride levels are too high (≥1.7 mmol/L or 150 mg/dL)
and HDL-C levels are too low (<1.0 mmol/L or 40 mg/dL). Niacin is a B
vitamin that has lipid-lowering effects at high doses. It inhibits the synthesis
and release of VLDL by the liver. Because VLDL gives rise to IDL and LDL,
plasma levels of these lipoproteins also fall. Conversely, HDL levels rise
significantly as a result of decreased breakdown, an effect which the ARBITER 2
study (2004) showed may slow the progression of atherosclerotic plaque in patients
with low HDL. Most patients experience flushing with niacin therapy. This is
due to vasodilatation caused by prostaglandin release from the endothelium, and
can be prevented by non- steroidal anti-inflammatory drugs. Other reported
adverse effects include hepatotoxicity, palpitations, impaired glucose
tolerance, hyperuricaemia, hypotension and amblyopia.
Fibrates include gemfibrozil, clofibrate, bezafibrate,
ciprofibrate and fenofibrate. Fibrates bind to peroxisome
proliferator-activated receptor alpha (PPARα) to stimulate the expression and
activity of LPL, thereby reducing VLDL triglycerides by increasing their hydrolysis.
They also promote changes in LDL composition, which render it less atherogenic,
and enhance fibrolysis. They cause mild gastrointestinal disorders in 5–10% of
patients, and can potentially cause muscle toxicity and renal failure if
combined with HMG-CoA reductase inhibitors or excessive alcohol use.
Bile acid sequestrants: bile
acids are synthesized from cholesterol in the liver, and cycle between the
liver and intestine (enterohepatic recirculation). Cholestyramine and cholestipol
are exchange resins that bind and trap bile acids in the intestine,
increasing their excretion. This enhances hepatic bile acid synthesis and
cholesterol utilization. The resulting depletion of hepatic cholesterol causes
an upregulation of LDL receptors, increasing the clearance of LDL-C from the
plasma. Bile acid sequestrants cause little systemic toxicity because they are
not absorbed. However, they must be taken in large amounts (up to 30 g/day) and
cause gastrointestinal side effects such as emesis, diarrhoea and reflux
oesophagitis, so are rarely used.
Ezetimibe reduces
absorption of dietary cholesterol by inhibiting the functioning of NPC1L1. This
reduces the plasma concentration and hepatic uptake of chylomicrons. The liver
responds to this by expressing more LDL receptors to maintain its cholesterol uptake, and
plasma LDL-C levels fall by ∼15%. Ezetimibe,
widely used together with statins, is a controversial drug, as the ENHANCE
(2008) and ARBITER 6 (2009) studies showed that this combination was no better
than a statin alone in reducing plaque progression, whereas a statin–niacin
combination was.
Anacetrapib simultaneously
lowers plasma LDL-C and strongly increases HDL-C by inhibiting CETP, and is
currently in Phase 3 trials for treatment of atherosclerosis.
