Hyperlipidaemia

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Hyperlipidaemia\: raised levels of TC, LDL-C, and TG in blood; a
Primary hyperlipidaemia\: often genetic; familial hypercholesterolaemia (FH) common, caused by LDLR gene mutations.
Secondary hyperlipidaemia\: hypercholesterolaemia (hypothyroidism, pregnancy, nephrotic syndrome, drugs);
hypertriglyceridaemia (type 2 diabetes, CKD, obesity, alcohol, drugs).
Symptoms\: usually asymptomatic; can present with acute pancreatitis if TG levels are very high.
Signs\: tendon xanthomata, xanthelasma, premature corneal arcus; indicative of underlying hyperlipidaemia or FH.
Investigations\: lipid pro
causes with speci
Diagnosis\: based on clinical
Clinical Network criteria.
Management\: lifestyle modi

Complications\: atherosclerotic complications (IHD, ACS, PVD, stroke, erectile dysfunction, mesenteric ischaemia); ADRs
from lipid-lowering drugs (rhabdomyolysis).
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A comprehensive topic overview

Introduction

Hyperlipidaemia refers to raised levels of one or more of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C)
and triglycerides (TG) in the blood.
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Dyslipidaemia is an umbrella term that includes hypercholesterolaemia, hyperlipidaemia and mixed dyslipidaemia. In
mixed dyslipidaemia, LDL-C and TG levels are elevated and often accompanied by low levels of high-density lipoprotein
cholesterol (HDL-C).
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Approximately 6 in 10 adults in England have serum cholesterol levels above 5 mmol/L.
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Heterozygous familial hypercholesterolaemia (FH) is one of the most common primary hyperlipidaemia with a
prevalence of between one in 250 and one in 500 in the UK.
Homozygous FH is rare with an incidence of one in a million.
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Aetiology

The causes of hyperlipidaemia can be divided into primary hyperlipidaemia and secondary hyperlipidaemia.
Primary hyperlipidaemiaMost cases of primary hyperlipidaemia are due to genetic factors interacting with environmental factors. However, single-
gene disorders may also be present.Familial hypercholesterolaemia is usually caused by mutations in the low-density lipoprotein receptor (LDLR) gene
which results in an autosomal dominant pattern of inheritance.
Secondary causes of hyperlipidaemia should be excluded before primary hyperlipidaemia may be diagnosed.
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Secondary hyperlipidaemia
The causes of secondary hyperlipidaemia can be further described based on the type of lipid that is elevated in the
blood\:
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Secondary hypercholesterolaemia\: hypothyroidism, pregnancy, nephrotic syndrome, anorexia nervosa and drugs (e.g.
diuretics, glucocorticoids, androgens, antiretroviral agents and ciclosporin)
Secondary hypertriglyceridaemia\: type 2 diabetes mellitus, chronic kidney disease, abdominal obesity, excess alcohol,
hepatocellular disease and drugs (e.g. beta-blockers, glucocorticoids, antiretroviral agents and retinoids)

Clinical features

History
Hyperlipidaemia is usually asymptomatic. Patients can present with features of acute pancreatitis such as sudden onset
of severe central abdominal pain often radiating to the back, shock, and abdominal skin discolouration due to signi
elevated levels of TG.
Important areas to cover in the history include\:
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Personal history of cardiovascular diseases and secondary causes of hyperlipidaemia
Family history of cardiovascular diseases, particularly at a young age (\<50 years old)
Smoking
Excess alcohol consumption
Obesity
Clinical examination
Some patients with hyperlipidaemia may develop signs including tendon xanthomata, xanthelasma and premature
corneal arcus.
Tendon xanthomata are hard, painless nodules commonly found on the knuckles of the hands and in the Achilles tendons
and rarely on the extensor hallucis longus and triceps tendons. The presence of tendon xanthomata, particularly over the
Achilles tendon, is pathognomonic of FH.
Xanthelasma (Figure 1) are lipid-laden nodules on the eyelids whereas premature corneal arcus (Figure 2) are bluish rims
surrounding the irises of the eyes.
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Figure 1. XanthelasmaFigure 2. Corneal arcus

Investigations

Lipid pro
A lipid pro
The TC/HDL ratio provides the best estimate of cardiovascular risk in a patient and is speciQRISK2 score
to calculate the 10-year risk of developing myocardial infarction or stroke in a patient.
Current NICE guidelines do not recommend a fasting sample to test for lipid pro
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Other investigations
Common secondary causes of hyperlipidaemia should be ruled out by ordering speci
table below.
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Table 1. Investigations for secondary hyperlipidaemia.
Secondary cause of
hyperlipidaemia
Excess alcohol Investigations
Uncontrolled diabetes
Hypothyroidism
Liver disease
Nephrotic syndrome
Liver function test to look for raised GGT
Fasting blood glucose, HbA1c both of which
would be elevated
Thyroid function test to look for raised TSH
and low T4 and T3
Liver function test to look for raised serum
AST, ALT, ALP and bilirubin
Urine dipstick to look for proteinuria
Liver function test to look for
hypoalbuminaemiaChronic kidney disease
Renal function test to look for raised serum
urea and creatinine

Diagnosis

NICE recommends that a diagnosis of hyperlipidaemia be made based on clinical
rather than the use of strict lipid cut‑o
Familial hypercholesterolaemia should be diagnosed based on the Simon Broome diagnostic criteria or the Dutch Lipid
Clinical Network (DLCN) criteria/score.
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Management

The management of hyperlipidaemia can be divided into conservative, medical and surgical and aims to reduce the risk of
cardiovascular diseases due to long-term uncontrolled hyperlipidaemia.
Conservative management
All patients with hyperlipidaemia should be encouraged to adopt several lifestyle modi
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Consume a diet low in saturated fats and cholesterol and high in fruits, vegetables, mono-and polyunsaturated fats
Exercise for at least 150 minutes per week with at least 30 minutes per day
Reduce alcohol intake to \<14 units per week for both men and women and avoid binge drinking
Stop smoking by enrolling on a smoking cessation programme
Medical management
Hyperlipidaemia due to secondary causes usually resolves following treatment of the underlying condition.
Lipid-lowering drugs play a key role in treating primary lipid disorders and for primary and secondary prevention of
cardiovascular diseases.
Table 2. Examples of lipid-lowering drugs and their mechanism of action are shown in the table below.
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Lipid-
lowering
drugs
HMG-CoA
reductase
inhibitors
(statins)
Bile acid
sequestrant
s
Examples Mechanism of action Indication
Atorvastatin,
simvastatin
Cholestyrami
ne
Inhibit conversion of
HMG-CoA to
mevalonic acid, a
cholesterol precursor
Prevents intestinal
absorption of bile
acids
Ezetimibe-
Prevents intestinal
absorption of
cholesterol
First-line for
hyperlipidaemia,
primary and secondary
prevention of
cardiovascular diseases
Considered if statins and
ezetimibe are
contraindicated
Second-line if statins are
contraindicated or as an
addition to initial statin
therapy for poorly-
controlled
hyperlipidaemiaFibrates
Gem
feno
Activates PPAR-𝛂 to
increase triglyceride
clearance and
increase HDL-C
synthesis
Considered if statins and
ezetimibe are
contraindicated
Niacin- Inhibits lipolysis
Considered if statins and
ezetimibe are
contraindicated
PCSK9
inhibitors
Alirocumab,
evolocumab
Inactivation of LDL-
receptor degradation,
hence increases LDL
clearance from the
blood
For poorly controlled
hyperlipidaemia despite
maximal tolerated lipid-
lowering therapy
For patients with FH or uncontrolled hyperlipidaemia despite the maximum amount of drug treatment and lifestyle
modi
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Surgical management
Liver transplantation can be considered for patients with homozygous FH with no signi
treatment with lipid-modifying therapy and LDL apheresis.
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Complications

If hyperlipidaemia is not diagnosed and treated early, major atherosclerotic complications can occur including\:
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Ischaemic heart disease
Acute coronary syndrome
Peripheral vascular disease
Stroke
Erectile dysfunction
Mesenteric ischaemia
Complications of lipid-lowering drugs
Complications may also occur due to adverse drug reaction (ADR) of lipid-lowering drugs, particularly statins and
The most severe form is rhabdomyolysis, a condition in which there is a breakdown of myocytes causing a release of
myoglobin and creatinine kinase into the bloodstream. If not treated early, this can lead to renal and multiorgan failure and
eventually, death.
Patients with rhabdomyolysis typically present with muscle pain and dark urine. A raised serum creatinine kinase at least 5
times the upper limit of normal is diagnostic.
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References

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h y p e r c h o l e s t e r o l a e m i a a n d m i x e d d y s l i p i d a e m i a . Published in May 2015. Available from\: [LINK]
National Institute for Care and Excellence Clinical Knowledge Summaries (NICE CKS). H y p e r c h o l e s t e r o l a e m i a – f a m i l i a l .
Published on September 2020. Available from\: [LINK]
r d
Ralston, S. H., Penman, I. D., Strachan, M. W. J., & Hobson, R. D a v i d s o n’ s p r i n c i p l e s a n d p r a c t i c e o f m e d i c i n e ( 2 3 e d i t i o n ) .
Published in 2018.
BMJ Best Practice. H y p e r c h o l e s t e r o l a e m i a . Published in April 2021.National Institute for Care and Excellence (NICE). C a r d i o v a s c u l a r d i s e a s e \: r i s k a s s e s s m e n t a n d r e d u c t i o n , i n c l u d i n g l i p i d
m o d i LINK]
Dr Colin Tidy. Published on 11 June 2021. Available from\: [LINK]
National Institute for Care and Excellence (NICE). F a m i l i a l h y p e r c h o l e s t e r o l a e m i a \: i d e n t i
Published on 27 August 2008. Available from\: [LINK]
t h
Dale, M. M., Rang, H. P. and Dale, M. M. R a n g a n d D a l e’ s p h a r m a c o l o g y ( 9 e d i t i o n ) . Published in 2020.
BMJ Best Practice. R h a b d o m y o l y s i s . Published in November 2019.

Reviewer

Dr Sarah Lontac Nufable BSBio, MD, DPCGGI, FPCGM, PGCMedEd(UK), FHEA(UK)
Associate Professor, Assistant Dean of Academic A

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Contents

Introduction
Aetiology
Clinical features
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