Introduction

Dyslipidaemia (often interchangeably used with hyperlipidaemia) describes raised levels of cholesterol in the blood. This is significant because it is associated with increased risk of cardiovascular disease.

Historically the management of raised cholesterol is a controversial topic – “the lipid hypothesis” is still challenged in some quarters even today. The landmark “Scandinavian Simvastatin Survival Study (1994) – aka “4S trial” proved survival benefit for lipid lowering therapies.

  • Multiple other studies have also shown this benefit – including the following trials; PLACI, PLACII, ACAPS, KAAPS, REGRESS
  • The INTERHEART study suggested that 45% of MIs are due to dyslipidaemia
  • Statins are the mainstay of treatment
  • Other lipid lowering drugs are more controversial – such as fibrates – as although they lower measurable cholesterol levels, they have not been associated with a reduction in cardiovascular disease

 

The lipid hypothesis suggests (and is strongly supported by epidemiological studies) that elevated levels of plasma cholesterol causes coronary artery disease as a result of pathological changes in artery walls.

Lipid lowering therapy reduces the incidence of stroke and coronary artery disease.

In particular, low density lipoprotein (LDL) is strongly correlated with coronary artery disease.

 

Classification

Dyslipidaemia refers to a state of an abnormal lipid profile in the blood. Can be:

  • Abnormally high triglycerides
  • Abnormally high cholesterol. Can be:
    • Total cholesterol – TChol
    • Low-density lipoprotein cholesterol – LDL-C
  • Abnormally high triglycerides and cholesterol
  • Abnormally low high-density lipoprotein – HDL-C
    • This is a risk factor for cardiovascular disease regardless of total cholesterol

Technically hyperlipidaemia refers only to increased levels of triglycerides and cholesterol and as such does not include reference to HDL-C. However in practice, the terms dyslipidaemia and hyperlipidaemia are often used interchangeably. 

 

Correlations

  • Risk increases with the degree of cholesterol elevation
    • 90% risk of cardiovascular disease in patients with total cholesterol >7.8mmol/L
    • 10% reduction in cholesterol gives a 20% reduction in cardiovascular disease risk after 3 years
  • Risk of cardiovascular disease particularly high in patients with high LDL and low HDL
    • LDL:HDL radio of >4, or HDL <1mmol/L indicates high risk
  • Triglycerides >10mmol/L associated with pancreatitis
  • LDL reduction with statin therapy reduces MI, stroke, death, and need for revascularisation therapies

Epidemiology

  • Extremely common in developed nations. In the UK almost two thirds of the adult population has a cholesterol >5.2 mmol/L. Mostly as a result of lifestyle and genetic factors
  • Familial hypercholesterolaemia (FH) is a specific genetic disease that causes elevated cholesterol, affecting about 1 in 500 individuals
    • Usually heterozygous
    • Homozygous disease is extremely rare
    • Consider this diagnosis in anyone with a total cholesterol of >7.5 mmol/L
    • Associated with a 4x increased risk on cardiovascular disease

Cause

Most cases are related to a combination of lifestyle and genetic factors. It is aslo important to consider secondary causes:

  • Hypothyroidism
  • T2DM
  • Cholestasis
  • Anorexia nervosa
  • Obesity
  • Alcohol excess
  • Liver disease
  • Renal disease
  • Medications
    • Thiazide diuretics
    • Corticosteroids
    • Beta-blcokers
    • Combined oral contraceptive pill
    • Antipsychotics

Presentation

Usually discovered incidentally on screening.

Levels are measured with a blood sample. A fasting sample is no longer routinely recommended – triglycerides may be falsely elevated in a non-fasting sample, but levels of total cholesterol, HDL-C and LDL-C are not thought to be significantly affected.

Consider specialist referral for patients with a total cholesterol >20 mmol/L. Levels of >10 mmol/L are associated with an increased risk of pancreatitis. Patients with these levels often have underlying familial hypercholesterolaemia. They may or may not present with the “textbook” signs of arcs senilis (white / grey / yellow ring around the margin of the cornea) and tendon xanthomata (hard, non-tender lumps in tendons – most commonly the achilles tendon).

Any patient with raised cholesterol should also have:

  • Fasting blood glucose – to exclude diabetes as a cause
  • Renal function – to exclude CKD as a cause
  • LFTs – to rule out liver disease as a cause, and because statin may be contraindicated if AST is >3x the upper limit of normal
  • TSH – to rule out myxoedema (hypothyroidism)

Diagnosing Familia Hyperlipidaema

The Simon Broom diagnostic criteria suggest a diagnosis can be made with:

  • TChol >7.5mmol/L AND
  • Tendon xanthomata in patient or first or second degree relative OR
  • DNA evidence of LDL receptor mutation

Offer DNA testing to anyone suspected of FH or diagnosed with FH. Offer DNA testing to family members of a patient with confirmed FH  particularly children of affected adults.

When to treat

Treatment should not be based purely on lipid levels. Typically, levels are used in association with a cardiovascular disease risk calculator (e.g. cvdcheck.org.au) to know when it is appropriate to treat. These calculators use multiple risk factors, including  age, gender, blood pressure, smoking history, left ventricular function (if known) and history of diabetes. The basic principles of these calculators involve treating patients with:

  • Known cardiovascular disease and total cholesterol >4mmol/L
  • High risk patients with total cholesterol >6.5mmol/L OR total cholesterol >5.5mmol/L and HDL <1mmol/L
    • T2DM
    • Familial hypercholesterolaemia
    • FHx of significant cardiovascular disease – first degree relative first diagnosed with cardiovascular disease at <60
    • Peripheral vascular disease
  • HDL <1mmol/L in ANY patient

In the example above (cvdchech.org.au – recommended in Australia) – patients should be treated medically when their 5-year risk exceeds 15%, and considered for medical treatment between 10-15% if they have failed or are unwilling to engage with lifestyle interventions.

Be aware that this calculator and many similar alternatives may underestimate risk – particularly as they do not take family history into account – and it may be necessary to make a clinical judgment in cases of a strong family history as described above.

Also be aware that the calculator can overestimate the risk on elderly men with no risk factors (purely based on age and gender) and may lead to over treatment in this age group.

Goals of treatment

  • Total cholesterol <4.0 mmol/L
  • HDL-C ≥1.0 mmol/L
  • LDL-C <2.0 mmol/L
  • TG <2.0 mmol/L

Non-pharmacological interventions

Dietary cholesterol accounts for between 10-40% of total cholesterol levels. Specific foods causing elevated cholesterol (e.g. eggs and butter) are probably less important than was previously thought, however the overall quality of the diet is still important.

  • Regular exercise
  • Smoking cessation
  • Alcohol intake <20mg daily (<2 standard drinks, and x2 alcohol-free days per week)
  • Weight loss
  • Advise of suggest waist measurements for minimising cardiovascular disease risk (<94cm for men and <80cm for women). This risk factor is independent of weight
  • Diet advice: aim for plant based, whole food diet. Minimise animal product and processed food intake. “Eat not too much, mostly plants”
    • Reduce animal fat intake – meat AND dairy
    • Diet high in vegetables and other plant based foods
    • Complex carbohydrates
    • Avoid deep fried food and “fast foods”
    • Steam and grill foods instead of frying
    • Avoid snacks heavy in calories (e.g. biscuits, cakes)
    • Eat fish at least twice per week
  • Can have a measurable effect in cholesterol in 6-8 weeks
  • Continue for at least 6 months before considering drug therapy, except in high risk patients

 

Medical Agents

Statins – e.g. atorvastatin, rosuvastatin, simvastatin

  • HMG-CoA reductase inhibitors
  • Adverse effects
    • Myalgias (most common)
    • GI upset
    • Abnormal LFTs
  • Do baseline LFTs and CK
    • Repeat at 4-8 weeks
    • Recommended to repeat every 6 weeks for 6 months after initiation of therapy

 

Alternative agents

  • Ezetimibe 10mg daily
    • Often used if statin not tolerated
  • Ezetimibe + statin
    • Often used if statin alone is not achieving control of cholesterol levels
  • Bile acid binding agents
    • Cholestyramine 4g daily – added to fruit juice (reduces side effects)
    • Causes GI symptoms including constipation and foul smelling wind!
  • Fibrates
    • Consider if above agents not working
    • Poor evidence – they lower cholesterol but studies suggest they do NOT improve cardiovascular outcomes
    • Thought to be more effective for triglyceride elevation
  • Nicotinic acid
    • 250mg BD with food
    • Can increase up to 1000mg TDS
    • Can cause gastric irritation, hot flushes and gout

 

Pregnancy

Pregnancy often causes a transient elevated of LFTs. This is not thought to be of clinical significance and should only be treated if it does not resolve after delivery

 

Dietary agents affecting cholesterol

Various dietary agents have been suggested as lowering cholesterol. Some of these have been studies.

  • Fish oils – consuming fish at least twice a week has been shown to lower cholesterol
  • Plant sterols – have also been shown to lower cholesterol
  • Other compounds, such as vitamin E, garlic and lecithin are not supported by evidence

References

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