Classification of dyslipidaemia

Diabetes is an important secondary cause of hyperlipidaemia though other lipid disorders may co exist in a patient with diabetes. The classification of dyslipidaemia provides a helpful method for determining the underlying cause of dyslipidaemia in a patient.

Laboratory analyses in dyslipidaemia

Classification of dyslipidaemia, as well as monitoring of treatment, relies on measurement of lipid profile and interpretation of the pattern of lipoprotein and apolipoprotein concentrations. Plasma lipoproteins vary considerably in size, composition and function and their measurement is therefore an analytical challenge.

Most clinical biochemistry laboratories routinely measure triglyceride, total cholesterol and HDL cholesterol concentrations. Triglyceride assays rely on a sequence of enzyme catalysed reactions in which triglycerides are hydrolysed to produce glycerol and fatty acids, and glycerol is subsequently phosphorylated and oxidised. Hydrogen peroxide is produced and measured after conversion to a coloured dye.

Total cholesterol assays also incorporate a sequence of enzymatic reactions. Enzymatic methods for measuring total cholesterol are accurate, precise and easily automated. These methods typically incorporate the cleavage of cholesteryl esters, oxidation of cholesterol using the enzyme cholesterol oxidase and subsequent measurement of hydrogen peroxide, similar to triglyceride assays. The methods can be subject to interference from other coloured compounds or those that compete for the oxidation reaction such as ascorbic acid.

Measurement of HDL cholesterol relies on a precipitation process to separate HDL from apo B containing lipoproteins (VLDL, IDL, LDL, chylomicrons and Lp (a)). A number of precipitating agents can be used including heparin sulphate with manganese chloride, dextran sulphate and polyethylene glycol. HDL in the supernatant solution is then allowed to react as described above for total cholesterol.

Methods for directly measuring LDL cholesterol are complex and expensive. They are generally used in research studies and by specialist lipid laboratories. The majority of clinical biochemistry laboratories estimate LDL concentrations using the Friedewald Equation:

LDL chol = Total chol – HDL chol – (Triglycerides/2.2), where all quantities are expressed in mmol/L. The factor (triglycerides/2.2) is an estimation of VLDL cholesterol concentration and is based on the average ratio of triglycerides to cholesterol in VLDL. The equation should not be used to estimate LDL cholesterol when serum triglyceride concentrations are greater than 4.5 mmol/L (though it has been shown that this method underestimates LDL at lower triglyceride concentrations and some laboratories will not report LDL concentrations if triglycerides are greater than 2 mmol/L).

Apoprotein B can be measured using immunoturbidimetric and immunonephelometric methods, where the protein is precipitated using specific antibodies and this results in changes in light absorption and light scatter respectively. The measurement of Apo B can help to identify patients with increased vascular risk and also monitor treatment of these patients. Apo B measurement is becoming increasingly popular as the limitations of LDL estimation described above are recognised.

Lipoprotein(a) (Lp(a)) is a class of lipoprotein that is structurally related to LDL; both particles have similar lipid composition and contain one molecule of apo B 100. Unlike LDL, each Lp(a) particle contains one molecule of apo(a), a protein that is covalently bound to apo B 100. Apo(a) shares significant peptide sequence homology with plasminogen and high plasma Lp(a) concentrations are an independent vascular risk factor. A variety of immunoassay techniques incorporating specific antibodies to Lp(a) have been developed, though it has been difficult to standardise these assays because of the structural heterogeneity of the Lp(a) particle. As a result, it has been difficult to compare Lp(a) values reported in different clinical studies and to define cut offs/target values that can be used to make clinical decisions.

Methods for classifying dyslipidaemia

Dyslipidaemia has been classified traditionally using patterns of lipoprotein abnormalities (Fredrickson classification, Table 1).

Table 1. Fredrickson classification of dyslipidaemia

Hyperlipoproteinaemia Elevated lipoprotein(s) Serum lipid pattern
Type I Chylomicrons Elevated triglycerides
Type IIa LDL Elevated cholesterol
Type IIb LDL and VLDL Elevated triglycerides and cholesterol
Type III IDL and chylomicron remnants Elevated triglycerides and cholesterol
Type IV VLDL Elevated triglycerides
Type V Chylomicrons and VLDL Elevated triglycerides and cholesterol

An alternative method for classifying dyslipidaemia divides conditions into primary or secondary hyperlipidaemia and characterises the conditions by the characteristic serum lipid pattern (elevated cholesterol or triglycerides or both). This has advantages over the Fredrickson classification (which is based primarily on the observed phenotype) because in some inherited hyperlipidaemias, the same genotype can be expressed as more than one phenotype and also, in some secondary hyperlipidaemias the phenotypes can vary.

Primary hyperlipidaemia

Primary hyperlipidaemias are caused by single or multiple gene mutations and a selection of the more common primary hyperlipidaemias is shown in Table 2.

Table 2. Examples of primary hyperlipidaemias and the associated lipoprotein abnormalities

Condition Genetic defect/mechanism Serum lipid pattern
Familial hypercholesterolaemia LDL receptor mutation, Apo B mutation, PCSK9 mutation Increased total chol and LDL (Fredrickson type IIa)
Polygenic hypercholesterolaemia Increased LDL particle number ± increased VLDL particle number Increased total chol and LDL (type IIa)
Familial combined hyperlipidaemia Increased VLDL particle number + increased small, dense LDL particle number Increased total chol and LDL (type IIa) or increased triglycerides (type IV) or increased total chol, LDL and triglycerides (type IIb)
Familial hypertriglyceridaemia Increased VLDL particle number Increased triglycerides (type IV)
Familial lipoprotein lipase deficiency Lipoprotein lipase mutation, Apo C-II deficiency Increased triglycerides, decreased HDL (type I)
Familial dysbetalipoproteinaemia Apo E2 homozygosity Increased total chol and triglycerides (type III)

Secondary hyperlipidaemia

In secondary hyperlipidaemia, the hyperlipidaemia is acquired (i.e. a complication of another disease or combination of patient factors). Examples of secondary hyperlipidaemias are shown in Table 3.

Table 3. Examples of secondary hyperlipidaemias and the associated lipoprotein abnormalities

Condition Serum lipid pattern
Diabetes mellitus Increased triglycerides, decreased HDL
Obesity Increased triglycerides, decreased HDL
Hypothyroidism Increased LDL, increased total chol, increased triglycerides (in some cases)
Chronic kidney disease Increased LDL, decreased HDL, increased triglycerides
Alcohol excess Increased triglycerides, increased HDL
Cholestasis Increased LDL, increased total chol

Diabetes Mellitus

Hyperlipidaemia in people with diabetes is associated with a greater risk of macrovascular disease than in the normal population. The following features are associated with type 2 diabetes, often preceding the stage at which blood glucose levels have risen into the diabetic range:

  • Increased triglycerides (increased VLDL production)
  • Low HDL cholesterol
  • Increased small, dense LDL

It is also important to remember that other primary or secondary causes of hyperlipidaemia may coexist in people with diabetes, and these should be screened for.


Abdominal obesity (more common in men) is associated with insulin resistance, hypertriglyceridaemia and elevated Apo B. VLDL levels are increased while HDL levels are decreased and in this form of obesity, the risk of cardiovascular disease is increased.


Serum LDL levels are raised in hypothyroidism because receptor mediated LDL catabolism is decreased. Triglycerides can be increased because LPL activity may be reduced. These abnormalities can be reversed after thyroxine replacement. There is also a tendency towards increased LDL concentrations in patients with subclinical hypothyroidism.

Chronic kidney disease

Both VLDL and LDL are increased in patients with chronic kidney disease and hypertriglyceridaemia is common. Heparin administration during haemodialysis can further exacerbate hypertriglyceridaemia by depletion of lipoprotein lipase and by loss of Apo C II from the circulation. Chronic ambulatory peritoneal dialysis can also exacerbate hypertriglyceridaemia as absorption of large amounts of glucose from the peritoneum can occur, resulting in obesity. Serum HDL levels are usually low in patients with chronic kidney disease. In nephrotic syndrome, the major lipid abnormalities are an increase in LDL and total cholesterol. Serum HDL levels are usually normal or decreased in nephrotic syndrome.


Excessive alcohol consumption can cause obesity and subsequent hypertriglyceridaemia. In addition, alcohol consumption increases hepatic triglyceride synthesis, VLDL secretion and fatty liver disease. Some patients with a tendency towards delayed triglyceride breakdown are at risk of extremely high triglyceride levels after alcohol consumption and this increases the risk of acute pancreatitis. In chronic excess alcohol consumption, HDL levels tend to be high with low LDL unless chronic liver disease has developed.

Liver disease

In cholestasis, hypercholesterolaemia occurs with elevated LDL levels. Moderate hypertriglyceridaemia may also occur. In hepatocellular disease, hypertriglyceridaemia occurs because of accumulation of lipoproteins intermediate between VLDL and LDL and this is caused by hepatic lipase failure and impaired removal of lipoprotein remnants.


A number of medications are associated with lipid abnormalities. Oestrogens increase serum triglycerides through increased hepatic VLDL production though the effect is usually small. Androgens decrease VLDL and HDL concentrations while increasing LDL. β blockers, especially non cardioselective β blockers, tend to increase serum triglycerides and decrease HDL levels. Thiazide diuretics increase VLDL and LDL concentrations. Long term therapy with the immunosuppressant cyclosporin causes elevated VLDL and LDL concentrations resulting in increased serum cholesterol and triglycerides. These changes are associated with an increased risk of atherosclerosis in these patients.

Anti retroviral drug regimens used in the treatment of HIV are associated with a number of metabolic complications including peripheral lipoatrophy, centripetal fat accumulation, hyperlipidaemia and glucose intolerance. The hyperlipidaemia is characterised by elevation of VLDL and chylomicrons, resulting in predominantly increased serum triglycerides. Apo B levels are elevated. VLDL hypersecretion occurs as a result of elevated plasma free fatty acid flux from insulin resistant peripheral tissues to the liver.

Further Reading:

Durrington PN. Secondary hyperlipidaemia. In: Hyperlipidaemia, Diagnosis and Management. Hodder Arnold, 2007: 310-360.

Remaley AT, Rifai N, Warnick GR. Lipids, lipoproteins, apolipoproteins and other cardiovascular risk factors. In: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Elsevier Saunders, 2012: 731 806.


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