Familial Hypercholesterolaemia: Case Finding, Assessment, and Management

Sadaf Qureshi and Dr Nadeem Qureshi Review Updated NICE Guidance on Familial Hypercholesterolaemia and Discuss the Importance of Proactive Identification of This Patient Group in Primary Care

Introduction

Over the past decade, it has become increasingly common to have cholesterol levels documented in general practice patient health records. A small number of individuals with very high cholesterol levels will have an inherited cause of raised cholesterol, known as familial hypercholesterolaemia (FH). Patients with FH have raised cholesterol levels since birth and this can lead to atherosclerotic disease, such as coronary heart disease (CHD), at an early age.¹ Familial hypercholesterolaemia is an autosomal dominant condition, meaning there are two forms of FH:¹

• heterozygous FH—the most common form of the disease, estimated to affect up to 1 in 250 people in the UK. In heterozygous FH, the defective gene is inherited from one parent, so if one parent is affected their children will have a 50% chance of inheriting the defective gene. If left untreated, FH can lead to coronary heart disease in over 50% of men by the age of 50 years and at least 30% of women by the age of 60 years. This can be prevented by starting high-intensity statins (see section on pharmacological management, below)
• homozygous FH—sometimes people can inherit the defective gene from both parents. Homozygous FH is rare, affecting 1 in 1 million people, and causes very high cholesterol levels in the blood. If homozygous FH is left untreated, CHD can develop in childhood.

In 2008 NICE published Clinical Guideline (CG) 71 on Familial hypercholesterolaemia: identification and management.^1,2 In 2015, NICE recognised that new evidence was available on: the identification of FH in different health settings (including primary care), the cost-effectiveness of genetic-based cascade screening, and treatment with high-intensity statins. To reflect the new evidence, NICE published an update to the guideline in November 2017.

Symptoms

Many people with FH (particularly young people) will show no signs or symptoms. Some people may have fatty deposits over the tendons of their hands, elbows, or knees (known as tendon xanthomata). The general lack of symptoms highlights the importance of case finding in primary care of this otherwise healthy general population.

Case Finding Heterozygous FH

Although people with heterozygous FH have a high risk of cardiovascular disease (CVD), they will usually have only one of the standard CVD risk factors (i.e. cholesterol level), and so their ‘increased risk’ status is not identified by standard CVD assessment tools, such as QRISK^® 3³ and JBS3.⁴

NICE CG71 emphasises the role of primary care in actively identifying adults with possible FH.¹ There is understandable concern that this could lead to excess GP workload. To keep this task manageable, the guideline recommends that GPs should only systematically search primary care records for people who are at the highest risk of FH. At the simplest level this is looking for:¹

• people aged <30 years with a total cholesterol >7.5 mmol/l
• people aged ≥30 years with a total cholesterol >9.0 mmol/l

These cholesterol levels are consistent with 99.5th percentile in the Health Survey for England 2003–2013.⁵

More sophisticated tools for searching patients’ electronic primary healthcare records have been developed to help identify people at highest risk of FH, including the familial hypercholesterolaemia case ascertainment tool (FAMCAT) and TARB-Ex.^6,7 This will help prioritise limited primary care resources.

As well as systematically searching for people at greatest risk, GPs should suspect FH in adults with:¹

• a total cholesterol level >7.5 mmol/l and/or
• a personal or family history of premature CHD (developing CHD before the age of 60 in an index individual or first-degree relative):
  • GPs should offer to measure total cholesterol in people in this group if this is currently unknown.

Once patients are identified, CG71 recommends that they are assessed and diagnosed against standard FH diagnostic criteria (see below).¹ Before considering a diagnosis of FH, however, practitioners should exclude secondary causes of hypercholesterolaemia, such as untreated hypothyroidism, cholestatic liver disease, and nephrotic syndrome.^1,8

Diagnosing Heterozygous FH

To make a clinical diagnosis of FH in primary care, GPs should use either the Simon Broome⁹ or Dutch Lipid Clinic Network (DLCN)¹⁰ criteria (see Box 1 and Table 1, respectively). These two diagnostic tools take account of:

• cholesterol level (total or, ideally, the low-density lipoprotein cholesterol [LDL-C] level)
• clinical signs suggestive of FH (e.g. tendon xanthomata, premature arcus cornealis)
• family history of CHD, raised cholesterol, or other clinical signs, with or without genetic test results.

Some patients will be classified as having definite FH (as categorised by Simon Broome, or a DLCN score >8), but most patients in primary care will be classified with possible/probable FH. Patients with a possible or definite FH diagnosis using the Simon Broome, or patients with DLCN scores >5, should be referred for specialist assessment.¹

Diagnostic Criteria for FH

The Simon Broome criteria (Box 1) is based on clinical, genetic and family history for the diagnosis of FH. A diagnosis of FH is categorised as ‘definite’ or ‘possible FH’.

The DLCN (Table 1) is a series of questions based on personal and family medical history, clinical signs, LCL-C concentration and DNA testing, with a score attributed to each component. The higher the score, the greater the likelihood of the person having FH.

Table 1: Dutch Lipid Clinic Network Score¹⁰

Diagnosing Homozygous FH

Most GPs will not see homozygous FH in practice, but this should be suspected if LDL-C concentrations are >13 mmol/l in adults and >11 mmol/l in children/young people. These individuals should be referred to specialist care for treatment.¹

Specialist Role in FH Diagnosis and Management

A diagnosis of FH is confirmed by a specialist through completion of a detailed three-generation family history, genetic testing, and repeating lipid profile measurements (including total cholesterol, LDL-C, and triglyceride levels). The 2017 update to CG71 emphasises that cascade testing may now be more cost effective than it was at the time of the guideline’s original publication in 2008.¹ As a result, it is now recommended that if diagnosis is confirmed, cascade testing (using a DNA test) should be performed to identify affected first-, second- and, if possible, third-degree biological relatives.

Pharmacological Management for Heterozygous FH

Treatment should be initiated by the FH specialist, with follow up and ongoing management handled by the GP. Homozygous FH should be managed under specialist care.

Note: Not all of the treatments discussed in this article currently (February 2018) have UK marketing authorisation for the indications mentioned. The prescriber should follow relevant professional guidance, taking full responsibility for all clinical decisions. Informed consent should be obtained and documented. See the General Medical Council’s guidance on Good practice in prescribing and managing medicines and devices¹² for further information.

Statins

People diagnosed with FH should be offered lipid lowering treatment. NICE CG71 recommends measuring liver and muscle enzyme levels before initiating statin therapy—this is usually undertaken by the FH specialist. The initial treatment of choice is a high-intensity statin (at the lowest possible acquisition cost).¹ In adults options include atorvastatin 20 mg+, simvastatin 80 mg, and rosuvastatin 10 mg+ (see Table 2).¹³

Table 2: Grouping of Statins Used in NICE Guideline 181¹⁴

The aim of the treatment is to achieve at least a 50% reduction in LDL-C concentration from the baseline measurement. If necessary, the statin dose may be increased to the maximum licensed or tolerated dose to achieve this.¹

Ezetimibe

Ezetimibe is a lipid-lowering treatment, which selectively inhibits the intestinal absorption of cholesterol. Ezetimibe is recommended as a treatment option either as monotherapy in adults who cannot tolerate statin therapy or for whom statin therapy is contraindicated, or for use in combination with a statin if lipid levels are still not adequately controlled after intensification of statin monotherapy.^1,15

Other Drug Treatments

Patients who are intolerant or have contraindications to statins or ezetimibe should be offered referral to an FH specialist. The specialist may prescribe a bile acid sequestrant or a fibrate.¹ Current British National Formulary (BNF) choices for bile acid sequestrants include: colesevelam, colestipol, and colestyramine. The fibrates include bezafibrate, ciprofibrate, fenofibrate, and gemfibrozil.¹⁶

PCSK9 Inhibitors

Other options, under specialist direction, include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which are monoclon­­­­­­­­­­­al antibodies that bind to and inactivate PCSK9 enzymes in the liver, ultimately helping to lower levels of LDL-C in the blood. This therapy is suitable in people whose LDL-C levels are not adequately controlled despite maximal tolerated lipid-lowering therapy. Two available options include alirocumab and evolocumab, the specific details for their use are described in NICE TA393¹⁷ and NICE TA394¹⁸ respectively.

Children and Young People

All children and young people diagnosed with or being investigated for a diagnosis of FH should be offered referral to specialist care.¹ Children by the age of 10 years (or at the earliest opportunity thereafter) should be considered for treatment with a statin that is licensed for use within their age group. Statin therapy should usually be prescribed at the doses specified in the BNF for children.^1,19

If there is a family history of CHD in early adulthood, an FH specialist can consider offering:¹

• a higher dose of statin than is licensed for use in the appropriate age group and/or
• more than one lipid-modifying therapy and/or
• lipid-modifying drug therapy before the age of 10 years.¹

Other lipid-modifying drug therapies such as bile acid sequestrants, fibrates, or ezetimibe may be offered to children/young people who are intolerant of statins.¹

Lifestyle Management

All people with FH should be offered lifestyle advice on smoking cessation (if applicable), consuming a healthy/low fat diet, and increasing physical activity. In summary this includes:¹

• diet—replace saturated fats with monosaturated and polyunsaturated fats, reduce total fat intake to ≤30% of total energy intake, and consume at least five portions of fruit and vegetables per day and at least two portions of fish per week (one of which should be oily)
• physical activity—at least 30 minutes of moderate activity at least 5 days a week
• smoking cessation—advise people with FH who smoke that they already have a greatly increased risk of CHD and should stop.

It is crucial to note that lifestyle interventions are not a substitute for lipid-lowering drug treatment.¹

Monitoring

There is no need for routine monitoring of creatine kinase in asymptomatic patients. A baseline electrocardiogram should be considered for adults with FH.¹

A structured annual review should be offered to all people with FH. This includes:¹

• recording results of cascade testing among the patient’s relatives
• updating the patient’s family history
• assessing any symptoms of CHD
• recording smoking status
• taking a fasting lipid profile
• enquiring about adherence to medication
• discussing any side-effects the patient may be experiencing from lipid-lowering treatment
• discussing any changes in lifestyle or lipid-lowering drug treatment that may be required to achieve recommended LDL-C concentration.

This review should initially be undertaken by the FH specialist, but eventually these patients could be discharged back to their GP. Patients should be referred back to specialist care if they develop CHD, there is a family history of premature CHD, and/or they have two or more other cardiovascular risk factors (e.g. smoker, hypertensive, diabetic).¹

Conclusion

In day-to-day clinical practice, GPs and practice nurses will come across patients with very high cholesterol levels. After excluding secondary causes, such as hypothyroidism and liver disease, practitioners should consider the possibility of FH. If FH is diagnosed and treated adequately, the patient’s risk of CHD can be dramatically reduced. Significant resources are used to perform standard CVD risk assessments in the adult population (e.g. NHS Health Check programme for people aged 40–74); however, this will not identify patients with FH and has much less impact, at a practice level, on preventing CHD compared with case finding for FH. 

Once diagnosis is confirmed and treatment commenced by an FH specialist, the patient will have an annual assessment under specialist care. At some stage of follow up, patients will be referred back to primary care to continue annual assessment. Any indication that atherosclerotic disease could have or has developed should lead to a referral back to the specialist. In summary, proactive identification and management can lead to improved quality of care for this group of patients at high risk of CVD.

Sadaf Qureshi

NICE Audit Pharmacist, NHS Southern Derbyshire Clinical Commissioning Group

Dr Nadeem Qureshi

Nottingham GP & Clinical Professor of Primary Care, University of Nottingham