HYPERLIPIDAEMIA

HyperlipidaemiaAdrian Park

AbstractHyperlipidaemia is very common and refers to the following biochemical

states: hypercholesterolaemia, hypertriglyceridaemia and mixed hyperli-

pidaemia. Hypercholesterolaemia is commonly polygenetically inherited.

Familial hypercholesterolaemia (FH) is commonly characterized by an

autosomal dominant low-density lipoprotein receptor mutation, with

significantly greater risk of premature cardiovascular disease (CVD).

Severe hypertriglyceridaemia (>10.0 mmol/litre, often diabetic and

alcohol-related) can cause pancreatitis. Potential causes of secondary

hyperlipidaemia have to be investigated. Serum fasting full lipid profile

and a baseline creatinine kinase should be performed. The management

includes treating and reassessing any underlying secondary cause,

addressing lifestyle and cardiac risk factors. It is important to determine

if treatment is needed for either primary or secondary prevention of CVD.

Statins are first-line treatment. In polygenic hypercholesterolaemia it is

important to assess the individual CVD risk. FH is diagnosed using the

Simon Broome criteria. In secondary prevention of CVD, it is important

to diagnose FH and treat with a statin to current guidelines (total choles-

terol <4.0 mmol/litre, low-density lipoprotein cholesterol <2.0 mmol/

litre). Statins are first-line therapy if triglycerides <6.0 mmol/litre. If

>6.0 mmol/litre, fibrates or high-dose fish-oils may be used. If severe

(>10.0 mmol/litre), consider fibrates and a very low-fat diet.

Keywords coronary vascular disease; hypercholesterolaemia; hyper-

lipidaemia; hypertriglyceridaemia; statins

Definition

There are three different types of hyperlipidaemia:

� hypercholesterolaemia, where a patient’s serum cholesterol

concentration necessitates treatment and can be for either

primary or secondary prevention of cardiovascular disease

(CVD)

� hypertriglyceridaemia, where a patient’s serum fasting

triglyceride concentration is elevated: can be defined as mild

(1.8e6.0 mmol/litre), moderate (>6.0e10.0 mmol/litre) or

severe (>10.0 mmol/litre)

� mixed hyperlipidaemia, where the patient has both an

elevated total serum cholesterol and triglyceride

concentration.

Pathogenesis

Dietary lipid is transported by chylomicrons from the gut to the

liver. The liver secretes very low-density lipoproteins (VLDL)

Adrian Park MBBS PhD MRCP FRCPath is Consultant Chemical Pathologist in

the Department of Clinical Biochemistry at Addenbrooke’s Hospital,

Cambridge, UK. Competing interests: an honorarium has been received

from Astra Zeneca for speaking at a general practitioner forum.

MEDICINE 37:9 49

into the circulation to provide cellular cholesterol and

triglyceride. As lipid is removed from VLDL, these become

denser, ultimately becoming proatherogenic low-density lipo-

proteins (LDL). Cholesterol is returned to the liver by LDL uptake

and by high-density lipoproteins (HDL).

Hypercholesterolaemia is frequently polygenetically inherited.

Familial hypercholesterolaemia (FH) is commonly characterized

by an autosomal dominant LDL-receptor mutation (heterozygote

frequency approximately 1 in 500).1 FH patients have a signifi-

cant risk of premature CVD.

Serum triglyceride is composed of both chylomicrons and

VLDL. Severe hypertriglyceridaemia can cause pancreatitis.

Diagnosis

Frequently, a patient presents with an abnormal lipid profile

detected on screening. In the history it is important to elucidate:

� personal history of CVD

� family history of CVD

� lipid-lowering therapy

� lifestyle (exercise and diet)

� smoking

� alcohol ingestion

� relevant medical history (e.g. hypertension, diabetes, HIV

infection, vasculitides).

Direct questioning should probe if there is a history of angina,

claudication, myopathy or abdominal pain. A full cardiovascular

assessment is required, noting tendon-xanthomas (hands, elbows,

knees and Achilles), xanthelasma, xanthomata and corneal arcus.

Investigations

Potential causes of secondary hyperlipidaemia have to be

investigated (Table 1). A fasting lipid profile (total cholesterol,

HDL-cholesterol, LDL-cholesterol triglycerides) and a baseline

creatinine kinase should be performed. If a fasting blood glucose

is greater than 5.6 mmol/litre, one should consider proceeding to

an oral glucose tolerance test. Urine should be dipsticked for

proteinuria. A baseline electrocardiogram is useful.

Types of hyperlipidaemia

See Table 1.

Management

General measures for all hyperlipidaemia

If a secondary cause underlies the hyperlipidaemia, treat this and

reassess. Lifestyle optimization is crucial, as is cardiac risk factor

control (notably blood pressure, diabetic control and smoking).

Females of child-bearing age should be counselled not to get

pregnant while on lipid-lowering medication and typically

require a 3-month wash-out prior to conception.

Specific management: hypercholesterolaemia

It is important to determine if treatment is needed for either

primary or secondary prevention of CVD.

Primary prevention of CVD: before treating polygenic hyper-

cholesterolaemia it is important to assess the individual CVD risk

using JBS2 charts,2 in conjunction with clinical assessment of all

7 � 2009 Published by Elsevier Ltd.

HYPERLIPIDAEMIA

risk factors (including family history, ethnicity and medical

history). Regular risk reassessment may be necessary. Treatment

without risk assessment3 should be considered in a patient with

a cholesterol:HDL ratio of 6 or above.

FH is diagnosed using the Simon Broome criteria on pre-

treatment cholesterol/LDL-cholesterol concentrations (Table 2).

If the patient has suspected FH there must be appropriate

counselling and family cascade screening (either genetically or

by age-specific cholesterol measurements).3,4

Statins are first-line treatment. In FH the aim is to achieve

a minimum of 50% LDL-cholesterol reduction (often using

atorvastatin or rosuvastatin) and treatment can lead to a normal

Different types of hyperlipidaemia with potentialsecondary causes of hyperlipidaemia listed3,7e10

Different types of hyperlipidaemia Potential causes of secondary

hyperlipidaemia

Secondary causes of

hyperlipidaemia

Renal impairment

Nephrotic syndrome

Hypercholesterolaemia:

polygenetically

inherited or FH*

Liver disease*

Mixed hyperlipidaemia

(either inherited

or part of the ‘metabolic

syndrome’)

Hypothyroidism

Hypertriglyceridaemia Diabetes mellitus

Obesity

Chronic excess alcohol

ingestion

Anorexia nervosa

Monoclonal gammopathy

Medication:

C anabolic steroids

C beta blockers

C ciclosporin*

C clozapine

C glucocorticoids

C interferons a-, b-, g-

C non-nucleoside reverse

transcriptase inhibitors*

C nucleoside reverse

transcriptase inhibitors*

C olanzapine

C progestins

C protease inhibitors*

C retinoic acid derivatives

C sirolimus*

C tamoxifen

C thiazide diuretics

FH, familial hypercholesterolemia.

* Patients should be referred to specialist lipid clinics if there is suspected

FH (including children) and other genetic hyperlipidaemias, significant

abnormal pre-treatment liver enzymes and secondary dyslipidaemia related to

transplantation or HIV-disease.

Table 1

MEDICINE 37:9 49

life expectancy.1 The shorter-acting statins are recommended to

be taken in the evening when they are slightly more effective

because cholesterol biosynthetic rates are greater nocturnally.5

This is unnecessary for the longer-acting statins (rosuvastatin

and atorvastatin).5 Second-line agents include ezetimibe and

bile-acid sequestrants. Patients should be monitored for statin-

induced rhabdomyolysis and hepatitis.

Secondary prevention of CVD: it is important to diagnose FH.

Treat with a statin (if tolerated) to current guidelines (total

cholesterol <4.0 mmol/litre, LDL-cholesterol cholesterol <2.0

mmol/litre or a decrease in LDL-cholesterol of 30%, whichever

gives the lower value).2 These targets are also for diabetics over

40 years of age or deemed high risk for CVD.

Specific management: hypertriglyceridaemia and mixed

hyperlipidaemia

Treatment and lifestyle changes for secondary causes (in partic-

ular alcohol intake and diabetes) are vital. The CVD risk should

be assessed.

If treatment is indicated, statins are usually first-line therapy

when triglycerides are less than 6.0 mmol/litre. Otherwise, for

mixed hyperlipidaemia fibrates can be used, although a statin-

fibrate combination may be needed (monitoring for rhabdo-

myolysis and hepatitis). High-dose fish-oils (e.g. omacor) are an

alternative to fibrates in moderate hypertriglyceridaemia.

If severe hypertriglyceridaemia does not respond to treating

secondary causes then consider fibrates and a very low-fat diet

(<25 g of fat/day).5 High-dose fish-oils and orlistat may also be

of use. Patients with a history of triglyceride-induced pancreatitis

are advocated preventative antioxidant therapy.6 A

The Simon Broome criteria for the diagnosis of FH

Definite diagnosis

A diagnosis of definite FH requires:

C cholesterol >7.5 mmol/litre in an adult (>6.7 mmol/litre in

children under 16) or LDL cholesterol >4.9 mmol/litre in adults

plusC tendon xanthomas in patient or first- or second-degree relative

or DNA-based evidence of an LDLR mutation, familial defective

apo B100, or a PCSK9 mutation.

Possible diagnosis

A diagnosis of possible FH requires:

C cholesterol >7.5 mmol/litre in an adult (>6.7 mmol/litre in

children under 16) or LDL cholesterol >4.9 mmol/litre in adults

plusC family history of MI before 60 years in first-degree relative

(before 50 years in second degree relative) OR cholesterol

>7.5 mmol/litre in first- or second-degree relative.

Pre-treatment lipid values are used.3,4

FH, familial hypercholesterolemia; LDL, low-density lipoprotein; MI,

myocardial infarction.

Table 2

8 � 2009 Published by Elsevier Ltd.

HYPERLIPIDAEMIA

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7 Mathis AS, Dave N, Knipp GT, Friedman GS. Drug-related dyslipidemia

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8 Fichtenbaum CJ. Coronary heart disease risk, dyslipidemia, and

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Acknowledgement

I would like to thank Dr Anita Sarker for the helpful comments on

the draft manuscript.

9 � 2009 Published by Elsevier Ltd.