My Clinical Notes

Lipoprotein metabolism

 

• Because lipids are insoluable, they are transported around the body as protein complexes called lipoproteins
• Lipoproteins are classified by their buoyant density which inversely reflects their size
• The greater the lipid:protein ratio, the larger the size and the lower the density

 

• Chylomicrons are the largest and the least dense lipoproteins and transport exogenous lipid from the intestine to cells (fasting lipid samples should not contain chylomicrons)
• VLDLs transport endogenous lipid from the liver to cells
• Intermediate-density lipoproteins (IDLs) are transient and form during the conversion of VLDL to LDL. They are not normally detectable in the plasma
• LDLs are formed from VLDL and carry cholesterol to the cells
• HDL are the most dense lipoproteins and are involved in the transport of cholesterol from the cells back to the liver (reverse cholesterol transport)
  • HDLs can be further subdivide into HDL2 and HDL3
• The first three are triglyceride rich whereas the last two contain mostly cholesterol

 

• The proteins associated with lipoproteins are called apolipoproteins
  • ApoA is the major group associated with HDL
  • ApoB group is predominantly found with LDL particles and is the ligand for the LDL receptor

 

Exogenous lipid pathways/Triglyceride metabolism pathway

• Cholesterol and fatty acids released from dietary fats, along with bile, are absorbed by the mucosal cells and re-esterified to form cholesterol esters and free fatty acids
• Together with phospholipids and ApoA and ApoB they are secreted into the lymph as chylomicrons

• Chylomicrons transport dietary triglyceride to the tissue, where it is removed by the action of lipoprotein lipase
• The resulting reminant particles are removed by the liver – they bind to reminant receptors (which recognised ApoE) on hepatic cells, are internalised and catabolised
• ApoA and B48 are synthesised in intestinal cells, ApoC and E are derived, together with cholesterol esters from HDL
• ApoC-II, activated lipoprotein lipase
• As cholesterol is removed from chylomicrons, ApoA, ApoC, cholesterol and phospholipids are released from the surfaces and transferred to HDL, where the cholesterol is esterified
• Cholesterol esters are transferred back to the chylomicron reminant in exchange for triglyceride by cholesteryl ester transport protein (CETP)
• Thus ultimately, the exogenous pathway delivers triglycerides to adipose tissue and muscles and cholesterol to the liver

 

Endogenous lipid pathways

• The liver is the main source of endogenous lipids
• VLDL consists of ApoB100, ApoC and ApoE
• VLDL is synthesised in the liver and transports endogenous triglyceride from the liver to the tissues where it is removed by the action of lipoprotein lipase
• At the same time cholesterol, phospholipids, ApoC and ApoE are released and transferred to HDL
• By this process VLDL is converted to IDL
• Cholesterol is esterified by HDL and the cholesteryl ester is transferred back to IDL by CETP
• Some IDL is removed by the liver but most has more triglyceride removed by hepatic triglyceride lipase to form LDL
• Thus the triglyceride rich VLDL are precursors of LDL which comprises mainly cholesterol ester and Apo-B100

 

• LDL are derived from VLDL via IDL
• They are removed by the liver and other tissues by a receptor dependant process involving the recognition of ApoB-100 by the LDL receptor
• The LDL particles are hydrolysed by lysosomal enzymes releasing free cholesterol which;
  • Inhibits HMG-CoA reductase
  • Inhibits LDL receptor synthesis
  • Stimulates cholesterol esterification by augmenting the activity of the enzyme acylCoA cholesterol acyl transferase (ACAT)

• Although most of the LDL is removed by LDL receptors, if the plasma cholesterol concentration is excessive, LDL particles due to their small size, can infiltrate tissues by passive diffusion and can cause damage, an example of which is atheroma formation

 

• Therefore the liver has an important role in cholesterol metabolism;
  • It contains most of the LDL receptors
  • It is responsible for most of the endogenous cholesterol synthesis
  • It takes up cholesterol from the diet via lipoproteins
  • It can secrete cholesterol from the body in bile
  • Cholesterol is synthesised by a series of enzymatic steps with HMG-CoA reductase being the rate limiting enzyme

 

• High density lipoprotein (HDL)
  • HDL is involved in the transport of cholesterol from non-hepatic cells to the liver in a process called reverse cholesterol transport
  • It is synthesised in the liver and intestinal cells and contains, free cholesterol, phospholipids , ApoA and ApoE
  • The cholesterol acquisition is stimulated by ATP binding cassette proteins 1(ABC1)
  • If the plasma concentration of VLDL or chylomicrons is low, HDL also carries ApoC, but as the concentrations of these lipoproteins rise, they take up ApoC from HDL
  • HDL can also be formed from the surface coat of chylomicrons and VLDL – various factors control this process including oestrogens
  • Lecithin-cholesterol acetyltransferase (LCAT) is present on HDL, is activated by ApoA and esterifies cholesterol
  • Most of the esterified cholesterol is transferred to VLDL, LDL and chylomicrons and end up back in the liver

 

 

 

Epidemiology

 

• HDL cholesterol is cardioprotective not only because of the reverse cholesterol transport  system, which helps to remove cholesterol from the peripheral tissues but also because it helps to increase atherosclerotic plaque stability, protects LDL from oxidation and maintains the integrity of the vascular endothelium
• A plasma HDL of less than 1mmol/L confers and increased cardiovascular risk and can be raised by lifestyle modification – smoking cessation, weight loss and exercise
• A low HDL is associated with DM Type II, obesity and insulin resistance syndrome
• The relationship between CHD and cholesterol is curvilinear – the curve becomes increasingly steep as cholesterol increases
• In individuals with other risk factors such as smoking, the curve is move upwards and is steeper – the risk factors are multiplicative
• Hypertriglyceridaemia is also a risk for CHD although probably a less important one
• High levels of homocysteine is a risk for artherosclerosis – seen in the inherited metabolic disease homocysteinuria which is associated with premature vascular disease
• This may be due to increased oxidation of LDL or direct toxic effects on the vascular endothelium

 

Secondary hyperlipidaemias

 

• Abnormalities are the result of an acquired condition
• Causes include;
  • Predominantly causing a hypercholesterolaemia
    • Primary hypothyroidism
    • Nephrotic syndrome
    • Cholestasis
    • Acute intermittent porphyria
      • Anorexia nervosa
  • Predominantly causing hypertriglyceridaemia
    • Alcohol excess
    • Obesity
    • DM
    • Chronic renal failure
    • SLE
    • Drugs – oestrogens, beta-blockers, thiazides

 

Primary hyperlipidaemias

 

Hypercholesterolaemia

 

Familial hypercholesterolaemia

• Characterised by the presence of high serum cholesterol levels that are present from childhood and do not depend upon the presence of environmental factors
• It is inherited as an autosomal dominant characteristic – prevalence of 1 in 500 of the population
• Different mutations effect LDL synthesis, transport, ligand binding, clustering in coated pits and recycling
• Familial defect in ApoB-100 gene, decreasing its avidity of LDL for its receptor has the same phenotype
• In heterozygotes the cholesterol is typically between 7.8 to 12mmol/L
• In the rare homozygotes, the plasma cholesterol concentration may be as high as 20mmol/L
• Triglyceride levels are generally normal
• These individuals develop coronary artery disease in childhood and rarely survive to adulthood
• Heterozygotes tend to develop coronary artery disease 20 years earlier than the general population and if untreated die on average before the age of 60
• They may present with xanthelasma, corneal arcus and tendon xanthomata
• Associated with atherosclerosis and aortic stenosis
• Treat with statins

 

 

Common (polygenic) hypercholesterolaemia

• Unlike familial hypercholesterolaemia where the distribution of cholesterol levels within a family are bimodal, more commonly when a family with hypercholesterolaemia are studied the levels of cholesterol follow a continuous distribution suggesting multiple genes are involved
• Plasma cholesterol is not as high as familial hypercholesterolaemia and are influenced to a greater extent by environmental factor

 

Hypertriglyceridaemia

 

Familial chylomicronaemia

• This can be due to either of two rare mutation;
  • One is a deficiency in lipoprotein lipase
  • The other is due to a deficiency in ApoC-II, required for the activation of lipoprotein lipase
• Results in failure to clear chylomicrons from the bloodsteam
• Presents in childhood with eruptive xanthomata, recurrent abdominal pain due to pancreatitis and sometime hepatosplenomegaly
• There is probably no increased risk of coronary artery disease
• Treatment is with a very low fat diet, sometimes with the addition of medium chain fatty acids which can be absorbed directly from the gut, not requiring chylomicron production

 

Familial hypertriglyceridaemia

• Due to increased synthesis for VLDL
• Inheritance is autosomal dominant
• If associated with other environmental factors, it may be associated with chylomicronaemia, in which case physical signs such as eruptive xanthomata and lipaemia retinalis may be present
• Uncertain if there is an increased risk of CHD, although levels of HDL are generally reduced
• In severe cases patients may present with pancreatitis

 

Both Hypercholesterolaemia and hypertriglyceridaemia

 

Combined familial hyperlipidaemia

• Due to hepatic overproduction of ApoB
• Either plasma cholesterol or triglycerides may be elevated or both
• Cutaneous manifestations of hyperlipidaemia may be present and all patients have and increased risk of coronary artery disease

 

Remnant hyperlipoproteinaemia

• Biochemically it is characterised by the presence of excess IDL and chylomicron remnants
• Clinically patients have fat deposits on their palmar creases and tuberous xanthomata, which occur over bony prominences and unlike tendon xanthomata are red in colour
• The palmar xanthromata are consider pathognomonic
• Total cholesterol and triglycerides levels are both elevated
• They are at risk of coronary artery disease and peripheral and cerebral vascular disease
• Associated with polymorphism in ApoE but the exact pathophysiology is not known

 

 

Investigations of hyperlipidaemia

• Ensure patient fasts for at least 12 hours before blood sample is taken (affects triglyceride levels more than cholesterol)
• Patient should be on his or hers normal diet for a few weeks preceding the test
• Don’t measure in anyone acutely ill as cholesterol concentrations may decrease during the acute phase response
• The usual fasting lipid profile consists of cholesterol, triglycerides and HDL
• LDL is calculated using the Friedewald formula;
  • LDL = Tot Cholesterol – HLD – triglycerides/2.2
• Determine alcohol intake from the history and also measure BM, LFTs, U&E’s and thyroid function to exclude secondary disease
• Do not rely on one set of readings – retest

 

Lipid lowering therapy

 

Hypercholesterolaemia

• Statins e.g. simvastatin and atorvastatin inhibit HMG-CoA reductase  and are used to treat hypercholesterolaemia
  • They decrease intracellular cholesterol concentrations, thus increases the LDL receptor expression and decreasing plasma LDL
  • These are the drugs of choice for hypercholesterolaemia
• Cholestyramine binds bile salts in the intestinal lumen, preventing their reabosrption, stimulating hepatic cholesterol synthesis which increases LDL receptor expression, resulting in a decreased plasma LDL concentration
• Ezetimbe inhibits intestinal cholesterol uptake
• Patients with familial hypercholesterolaemia tend to respond badly to drugs and are treated by repeated plasma apheresis, a process that physically removes the LDL from the circulation
  • They may also be treated by liver transplantation

 

Hypertriglyceridaemia

• May respond well to controlling body weight and any coexisting exacerbating factors such as excess alcohol intake
• Drugs of choice are;
  • Fibrate drugs act as PPARα agonists which increased lipoprotein lipase activity
  • Nicotinic acid reduces VLDL and LDL concentrations
  • Omega 3 fatty acid  in the form of fish oils or flaxseed oils reduce VLDL synthesis and can be used to treat severe hypertriglyceridaemia

 

• Specialist lipid assays may help define the abnormality;
  • ApoE genotype for patients with suspected remnant hyperlipoproteinaemia
  • Lipoprotein lipase and ApoC-II assays for chylomicron syndrome
  • LDL receptor DNA studies for familial hypercholesterolaemia

 

This entry was posted on Sunday, March 9th, 2008 at 3:46 pm and is filed under Chemical Pathology. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.