2nd April 2024

Hyperlipidaemia

Hyperlipidaemia

Hyperlipidaemia is caused by abnormally high levels of lipids in the blood. Cholesterol and triglycerides are the primary circulating forms of lipids in the body and are insoluble.

In the UK, nearly 40% of the population has high or borderline high LDL cholesterol levels. Hypercholesterolemia is associated with an increased risk of cardiovascular events, including myocardial infarction, coronary artery disease, vascular disease, and stroke due to atherosclerosis. Early detection and treatment are essential to reducing cardiovascular events and mortality.

Pathophysiology

Cholesterol synthesis involves multiple steps (see image below), beginning with acetyl CoA. These steps are reversible up to the rate-limiting step, where the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, synthesises mevalonate from HMG-CoA. Statins such as simvastatin work at this rate-limiting step and reduce the production of LDL cholesterol through the inhibition of HMG-CoA reductase.

Image source: Lumen Learning (2024). Cholesterol synthesis simplified, Licensed under a Creative Commons licence. Available for free at:  https://courses.lumenlearning.com/suny-nutrition/chapter/6-35-cholesterol-synthesis/ (Accessed: 28 January 2024).

Lipoproteins

Lipid is carried in the blood by lipoproteins composed of proteins, lipids, and phospholipids. They are found in the plasma and bind lipids, converting them from an insoluble to a soluble form. Apoproteins are the protein component of lipoprotein and act as receptors, ligands, and coenzymes. Table 1 shows the different types of lipoproteins.

Table 1: Types of lipoproteins

Clinical manifestations 

Hyperlipidaemia is usually asymptomatic and diagnosed by performing a blood lipid profile. This may be a routine test or requested specifically, where patients present with the consequences of having high lipids (stroke, MI). Small non-tender fatty deposits called xanthelasma may be seen around the eyes, although these can be seen in those without hyperlipidaemia. 

Xanthomas contain cholesterol and fat deposits that occur in cases of chronic cholestasis (more than three months). There are various types that can involve bone and peripheral nerves: 

• Palmar xanthoma – yellow discolouration of palmar creases seen in remnant hyperlipidaemia, less commonly in familial hypercholesterolaemia.
• Eruptive xanthoma – high triglyceride levels result in red/yellow vesicles to extensor surfaces of knees and elbows. This is seen in familial hypertriglyceridemia and lipoprotein lipase deficiency.
• Tendon and tuberous xanthoma. Seen in familial hypercholesterolaemia and remnant hyperlipidaemia. 
• Xanthoma treatment options include topical trichloroacetic acid, surgical excision, laser therapy, and electrodesiccation.

Classification 

The Fredrickson classification for hyperlipidaemia is summarised in Table 2. 

 Table 2: Modified Fredrickson Classification of Hyperlipidemia. Adapted from Berberich et al (2013)

Type I: Familial Chylomicronaemia

This is a rare autosomal recessive disorder due to mutations in the lipoprotein lipase (LPL) or apolipoprotein C-II gene, which prevents the body from breaking down triglycerides and dietary fats. Chylomicrons and triglycerides are elevated, but the high levels do not appear to confer an increased risk of atherosclerotic disease. Clinical features include cutaneous eruptive xanthomas, steatorrhea, lipemia retinalis, recurrent pancreatitis, and blood that appears ‘milky’ when drawn. Symptom onset can vary, appearing in infancy, early childhood, or adolescence. The long-term effects include chronic pancreatitis and type 2 diabetes mellitus.

Type IIa: Familial Hypercholesterolemia (FH)

This autosomal dominant disorder results in absent or defective LDL receptors and is caused by a mutation on chromosome 19, where the LDL receptor gene is located. The body is unable to clear LDL cholesterol from circulation, resulting in high blood levels of LDL and total cholesterol with normal triglyceride levels. Those affected may be homozygous or heterozygous, with tendon xanthomata being diagnostic for heterozygous familial hypercholesterolaemia, which occurs in about 70% of affected people. Xanthelasma and premature corneal arcus are common but unspecific signs. Homozygous FH is a rare condition with symptoms appearing in childhood; most patients die early from coronary artery disease.

Type IIb: Familial Combined Hyperlipidaemia (FCH)

This is the most common heritable lipid disorder found in approximately 1 in 100 people. It is characterised by high cholesterol and triglyceride levels from elevated LDL and VLDL, and can cause early myocardial infarction in those affected. Physical signs such as xanthomas or xanthelasmas are uncommon, and it is closely linked to hypertension, type 2 diabetes mellitus, and the development of gout.

Treatment is with statins, which may be combined with fibrates in addition to lifestyle modifications, including a healthy weight and diet. 

Type III: Remnant Hyperlipidaemia

Also known as Fredrickson type III hyperlipidaemia and dysbetalipoproteinaemia, this is a rare condition characterised by total cholesterol of >10 mmol/L and triglyceride levels of 4-8 mmol/L. It is due to a combination of abnormal ApoE receptor function and metabolic disorders such as diabetes, obesity, and hypothyroidism. 

Homozygous individuals for ApoE2 have a 1-2% risk of developing remnant hyperlipidaemia and are at risk for early-onset atherosclerotic disease due to high levels of chylomicron remnants and IDL in the blood. Type III is distinguished from type IIb hyperlipidaemia by elevated IDL levels in type III. 

Clinical manifestations include tuberous and palmar xanthomata and premature vascular disease. 

Management involves the correction of metabolic abnormalities (diabetes, obesity, and hypothyroidism), lipid-lowering medications, and lifestyle modification.

Type IV: Familial Hypertriglyceridemia

This autosomal dominant condition is characterised by raised triglyceride levels and normal or mildly raised cholesterol. VLDL is also elevated due to overproduction and decreased removal by the liver. Typically, plasma triglyceride levels are moderately elevated, ranging from 2.3 – 5.7 mmol/L. Patients are usually asymptomatic, but there is an increased risk of obesity, diabetes mellitus, hypertension, and cardiovascular disease. After dietary modification, fibrates are used as first-line treatment.

Type V: Primary Mixed Hyperlipidaemia

Characterised by elevated chylomicrons and VLDL. The clinical manifestations are similar to Type I familial chylomicronaemia, but they develop in adulthood. Triglyceride levels are usually > 11.3 mmol/L, along with raised total cholesterol levels and low LDL-C. Due to the rarity of type I disease, triglyceride levels > 11.3 mmol/L are likely to be due to type V hyperlipidaemia. This is associated with conditions including: 

• Diabetes mellitus
• Hypothyroidism
• Excess alcohol use
• Glycogen storage disease type I
• Hyperuricemia
• Pancreatitis
• Eruptive xanthoma
  

The aim of treatment is to reduce triglyceride levels to < 5.6 mmol/L, as there is an increased risk of acute pancreatitis when levels are > 11.3 mmol/L.

Diagnosis  

Simon Broome’s diagnostic criteria for FH include cholesterol levels, clinical characteristics, molecular diagnosis, and family history. A definitive diagnosis of FH is made when:

• Total cholesterol > 6.7 mmol/L or LDL-C > 4.0 mmol/L in a child aged younger than 16 years OR 
• Total cholesterol > 7.5 mmol/L or LDL-C > 4.9 mmol/L in an adult PLUS at least one of the two:
  • Tendon xanthomas in first- or second-degree relatives OR
  • DNA evidence of LDL receptor mutation, familial defective apo-B-100, or PCSK9 mutation

FH may be suspected with the cholesterol values above, plus one of the following:

• Myocardial infarction at age 60 years or younger in a first-degree relative or age 50 years or younger in a second-degree relative OR
• Total cholesterol > 7.5mmol/L in a first or second-degree adult relative or > 6.7mmol/L in a child, brother, or sister less than 16 years.

Cardiovascular risk assessment 

The QRISK assessment is a primary prevention tool used to evaluate the 10-year CVD risk in those up to and including age 84. Statin therapy, usually atorvastatin 20 mg daily, should be offered to those with a total CVD risk of over 10%. 

Those over age 85 or who have existing CVD, T1DM, CKD or familial hypercholesterolemia do not require QRISK stratification as they are regarded as at increased risk of CVD events. 

All adults with T1DM aged over 40 years, or who have had diabetes for more than 10 years or, established nephropathy, or with other CVD risk factors, are recommended 20 mg daily of atorvastatin.

Management 

Lifestyle modification is the first line in the management of hyperlipidaemia. This involves regular exercise, maintaining a healthy weight, smoking cessation, sensible alcohol consumption, and a healthy diet. After lifestyle modification, statins are the mainstay of treatment. Statins are effective when taken at night as this coincides with peak endogenous cholesterol synthesis. Other pharmacological options include niacin, bile acid sequestrants, fibrates, and ezetimibe.

All patients with FH should be referred to a lipid clinic and started on lipid-lowering therapy, titrated until there is a 50% reduction in LDL cholesterol. NICE guidelines recommend increasing simvastatin to 80 mg if total cholesterol of < 4 mmol/L or LDL cholesterol of < 2 mmol/L is not attained. 

Statins should be discontinued in women three months before conception due to the risk of congenital defects. 

Other treatment options include plasma exchange to reduce plasma LDL by extracorporeal removal. Liver transplantation may be offered for patients who already have had maximal medical therapy. 

Screening of first-degree relatives is recommended as they have a 50% chance of having FH. Untreated FH causes coronary heart disease in 50% of men by age 50 and 30% of women by age 60. 

Secondary hyperlipidaemia

Secondary causes of dyslipidaemia, shown in Table 3, should be identified and managed once hypertriglyceridemia has been diagnosed.

Table 3. Causes of secondary dyslipidaemia

References

• Berberich, 2013. Fredrickson dyslipidemia classification. Available at: https://www.researchgate.net/figure/Fredrickson-Dyslipidemia-Classification_tbl2_236076966
• Lumen learning. 2022. Cholesterol biosynthesis. https://courses.lumenlearning.com/suny-nutrition/chapter/6-35-cholesterol-synthesis/
• Simon Broome classification in FH – General Practice notebook. https://gpnotebook.com/simplepage.cfm?ID=x20100223155634200186
• Cardiovascular risk assessment and lipid modification. https://www.nice.org.uk/guidance/qs100/chapter/quality-statement-1-full-formal-risk-assessment-using-qrisk2.
• Cardiovascular disease: risk assessment and reduction. https://www.nice.org.uk/guidance/cg181/resources/cardiovascular-disease-risk-assessment-and-reduction-including-lipid-modification-pdf-35109807660997.

Hyperlipidaemia medications

After lifestyle modifications, statins play a major role in treatment of hyperlipidaemia and are effective when taken at night, coinciding with peak endogenous cholesterol synthesis. Other lipid regulators include niacin, bile acid sequestrants, fibrates, and ezetimibe.

Statins

Statins, such as simvastatin, work by competitively inhibiting HMG-CoA reductase to reduce hepatic cholesterol synthesis. They are most effective at lowering LDL-C but less effective than fibrates at lowering triglyceride levels. Common side effects include fatigue, headache, nausea, indigestion, and change in bowel habits. Significant but rarer side effects include statin-induced myopathy, hepatotoxicity, and statin-induced diabetes. 

Statin-induced myopathy incorporates the spectrum of myalgia, myositis, rhabdomyolysis, and raised creatine kinase (CK). The mean duration of treatment before the onset of symptoms is six months. It affects 10-15% of patients and is characterised by muscle and tendon pain, stiffness, and cramping. Although rare, it may lead to life-threatening rhabdomyolysis. The risk of statin-induced myopathy is increased by:

• Dietary intake of grapefruit or cranberry juice.
• Co-prescription of drugs that inhibit cytochrome P450 CYP3AE (fibrates, nicotinic acid, calcium-channel blockers, ciclosporin, amiodarone, macrolide antibiotics, azole antifungals, and protease inhibitors). 
• Genetic factors, such as polymorphisms in cytochrome P450 isoenzymes that increase the risk of statin-induced myopathy

CK levels are not routinely monitored unless the patient is symptomatic. Where the patient describes symptoms and CK levels as normal, this is termed myalgia. Statin-induced myositis is diagnosed in symptomatic patients where the CK levels are < 10 x the upper limit of normal. In rhabdomyolysis, CK levels are >10 times the upper limit of normal. In addition, the urine will appear brown due to the presence of myoglobin. 

Several factors contribute to the risk of rhabdomyolysis, including older age (≥65 years), renal impairment, and uncontrolled hypothyroidism.

Hepatotoxicity is rare, reversible, and dose-dependent. It is characterised by a rise in AST and ALT < 3 times the upper limit of normal and usually occurs in the first three months of treatment. Statins do not need to be stopped at this level. Should transaminases rise > 3 times the upper limit of normal, statin therapy should be temporarily stopped before rechallenging or reducing the dose with closer monitoring. LFTs should be repeated after three months of statin treatment, after dose increases, and at one year. 

There is a recognised link between statin use and new-onset diabetes in 10-12% of patients. The mechanism is thought to involve insulin resistance and insulin secretion, and the main risk factors identified were age ≥60 years, rosuvastatin therapy, higher doses, and longer duration of statin therapy.

Lipid regulating medications

Table 4 shows commonly used medications for hyperlipidaemia, and Table 5 summarises additional lipid-regulating medications.

Table 4: Medications for hyperlipidaemia

Table 5: Additional lipid-regulating drugs

Bempedoic acid is a new non-statin drug taken orally in combination with ezetimibe in patients with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidaemia. NICE recommends this as an adjunct to diet in adults where statins are contraindicated or not tolerated or, where ezetimibe alone has failed to control LDL cholesterol. 

Inclisiran, a PCSK-9 inhibitor, can be given as an injection bi-annually to lower LDL cholesterol. NICE recommends this as an option for treating primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults where LDL cholesterol concentrations are persistently >2.6 mmol/ L despite maximum tolerated lipid-lowering therapy and if the patient has any of the following CVD risk factors: 

• ACS
• CAD/PAD
• Coronary or other arterial revascularisation procedures 
• Ischaemic stroke

References

• Calculation of cardiovascular risk in type 1 and 2 diabetes. Available at: https://primarycarenotebook.com/simplepage.cfm?ID=x20150114153930862850.
• Inclisiran for treating primary hypercholesterolaemia. Available at: https://www.nice.org.uk/guidance/ta733/resources/resource-impact-summary-report-9259730749.
• NICE recommendations on use of statins for prevention of CVD. 
• Available https://www.nice.org.uk/News/Article/nice-recommends-wider-use-of-statins-for-prevention-of-cvd
• Shattat, G.F., 2015. A review article on Hyperlipidemia: Types, treatments and new drug targets. Biomedical and Pharmacology Journal. Available at: https://biomedpharmajournal.org/vol7no2/a-review-article-on-hyperlipidemia-types-treatments-and-new-drug-targets/