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.

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) levels (“bad cholesterol”) are strongly correlated with coronary artery disease, whilst HDL –  high density lipoprotein (“good cholesterol”) is protective.

Elevated cholesterol is typically discovered in screening blood tests. The decision to treat depends on multiple factors, which as usually assessed using a cardiovascualr scoring system, such as QRISK3 (UK) or CVDCHECK (AUS).

Exercise and changes in diet can effectively lower cholesterol. Statins are the mainstay of medical 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.

A new class of injectable drugs – known as PCSK9 inhibitors have been around since the last 2010s. These show good results in trials but are expensive and require an injection – but are useful in difficult to treat cases.

The Lipid Hypothesis

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

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 of cardiovascular disease

Causes

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

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

Presentation

Usually discovered incidentally on screening.

• Australian guidelines (RACGP red book) recommends that every adult have their cholesterol checked every 5 years from age 45 onwards
  • Every 2 years if CVD risk >10%
  • Every year if CVD risk >15%

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.

It is recommended to have two separate samples at different times to confirm the diagnosis.

• One of these should be fasting

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.

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)

“Normal” cholesterol level

A normal cholesterol level depends on the individual.

• No known cardiovascular disease – LDL <4, total cholesterol <5.5
• Known cardiovascular disease – LDL <2, total cholesterol <4

In individuals with no known cardiovascular disease with a raised cholesterol, if the overall cardiovascular risk remains low, there may not be large benefit from pharmacological management, but these patients should still be encouraged to lower their cholesterol with lifestyle factors.

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. QRISK3or 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. High risk include:
  • 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 phamacologically when their 5-year risk exceeds 15%, and considered for pharmacological treatment between 10-15% if they have failed or are unwilling to engage with lifestyle interventions.

Be aware that the CVDCHECK 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.

• QRISK3 is more in-depth and includes this amongst other factors

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.

Refer patients with any of the below for investigation for familial hypercholesterolaema:

• Total cholestoler >8mmol/L
• Total cholesterol >6mmol/L with FHx of premature ischaemic heart disease
  • ‘Premature” defined as – age of onset <55 in men or <60 in women
• Known FHx of a genetic lipid disorder

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

In familial hypercholesteolaemia

• Aim to reduce LDL-C by 50%

Cholesterol levels can be re-checked 6 weeks after an intervention.

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 foods high in saturated fat
    • 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
  • ”Mediterranean Diet”
• 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
  • Ezetemibe binds to cholesterol in the digestive tract and can reduce LDL by up to 15%
• 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

PCKS9 inhibitors

• PCSK9 – propotein convertase subtilisin/kexin type 9 – inhibitors are relatively new (around since late 2010s)
• Require an injection
• Examples are alirocumab (Praluent) and evolocumab (Repatha)
• Extremely expensive – in 2018 the quoted annual price was around $14,000USD per year. This is likely to fall and their use is likely to become more prevalent
• May be indicated in particularly difficult to treat cases – especially those involving familial hypercholesterolaemia
• Proven to reduce heart attack and stroke risk by about 15%

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 to lower cholesterol. These include:

• 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

Familial Hypercholesterolaemia

Familial hypercholesterolaemia – FH (aka familial hyperlipidaemia) is an inherited, autosomal dominant disorder. It is a common, but under diagnosed disorder, often encounter in general practice. It affects about 1 in 250 people, and 50% of all first degree relatives of an affected individual.

• Only about 10% of cases are formally identified

It results in massively elevated cholesterol levels from birth, which leads to the early development of cardiovascular disease.

• Cardiovascular disease risk is up to 25x greater than the general population

Patients may or may not present with the “textbook” signs of:

• Arcus senilis – white / grey / yellow ring around the margin of the cornea. Commonly seen in healthy older individuals, but pathological if found at age <45
• Tendon xanthomata – hard, non-tender lumps in tendons – most commonly the achilles tendon
• Xanethelasma – fatty deposits around the eyes

Occasionally (and I have seen it) when a blood sample is taken is can appear yellow and fatty in the test tube!

There is usually a strong family history of raised cholesterol and early onset cardiovascular disease. Early onset cardiovascular disease is defined as:

• Coronary artery disease in men aged <55
• Coronary artery disease in women aged <60

All FH patients should be follow-up annually to check the cholesterol levels and to investigate for any evidence of cardiovascular disease. Compliance, particularly in young asymptomatic patients can be difficult.

Diagnosing Familial Hypercholesterolaemia

Once other possible causes have been excluded – such as hypothyroidism, corticosteroid use, renal disease (nephrotic syndrome) and diabetes, then you can assess the patient for FH.

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

Other scoring systems (such as the Dutch Lipid Clinic Network Criteria – DLCNS) are also used – and are more complex. Online calculators are available. Genetic testing is not always required if a scoring system suggests a diagnosis of FH. If there is doubt over the diagnosis, then offer DNA testing. Also consider offering DNA testing to family members of a patient with confirmed FH particularly children of affected adults.

• Cascade screening is the term used to describe the screening process for relatives on an “index case” of familial hypercholesterolaemia
• It usually involves a genetics specialist, and discussion with family members about the sharing of confidential information, and the legal and ethical implications of sharing genetic information ith asymptomatic family members.

Elevated Triglycerides

Elevated triglycerides, especially with otherwise normal lipid profile is strongly correlated to lifestyle factors. Triglycerides also vary more widely between a fasting and a non-fasting sample.

Elevated triglycerides may falsely alter the result of LDL (often making it appear falsely low)

If elevated to >5 mmol/L:

• Advise lifestyle changes, and re-check, ensuring a fasting sample
• Consider fibrates

Flashcard

References

• Familial Hyperlipidaemia – RACGP
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Hyperlidipaemia – patient.info
• Managing Lipids – NPS MedicineWise

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