REVIEW URRENT C OPINION
Familial hypercholesterolaemia Devaki R. Nair a, Mahtab Sharifi a, and Khalid Al-Rasadi b
Purpose of review Familial hypercholesterolaemia is associated with lifelong elevated cholesterol levels and is an important cause of premature coronary heart disease (CHD). This condition is often underdiagnosed and undertreated. Awareness of this condition is poor among nonlipid specialists. Treatment of elevated cholesterol levels with statins reduces the risk for CHD. The review will increase the awareness of this condition among nonspecialists. Recent findings Recently, several guidelines have been produced by different countries, but a unified approach to this global problem is addressed through a recent guideline facilitated by the Familial Hypercholesterolaemia Foundation. Although the widespread use of statins has been successful in reducing the risk for CHD in familial hypercholesterolaemia, there have been difficulties in getting to targets, especially in those with established vascular disease. New therapies such as mipomersen, a second-generation antisense oligonucleotide, microsomal triglyceride transfer protein inhibitors that decrease the synthesis of apolipoprotein B-containing lipoproteins and proprotein convertase subtilisin/kexin type 9 inhibitors hold promise in reducing cholesterol levels in those patients in whom low density lipoprotein cholesterol (LDL-C) reduction is required beyond the use of statins, especially in those with severe heterozygous familial hypercholesterolaemia or homozygous familial hypercholesterolaemia. Summary Increased awareness and wider availability of guidance to treat familial hypercholesterolaemia will improve management of familial hypercholesterolaemia. New therapies, if they become available after appropriate outcome studies, will reduce LDL-C levels in both homozygous familial hypercholesterolaemia and severe heterozygous familial hypercholesterolaemia, thus reducing the risk for premature CHD. Keywords familial hypercholesterolaemia, guidelines for familial hypercholesterolaemia, premature coronary heart disease
INTRODUCTION Familial hypercholesterolaemia is an autosomal dominant condition characterised by high low density lipoprotein cholesterol (LDL-C) concentration and a high risk for premature cardiovascular disease (CVD) [1 ,2]. The cumulative risk for fatal or nonfatal cardiac events is approximately 50% in men and 30% in women by 60 years of age in those with heterozygous familial hypercholesterolaemia (HeFH). In those under 40 years old, the relative risk for a nonfatal cardiac event is 100-fold greater than that for the general population [3]. The prevalence in Europe of HeFH is estimated to be 1 in 500 (and may be as common as 1 in 250), and for homozygous familial hypercholesterolaemia (HoFH) one in a million [4]. These figures may be higher in some populations, especially if there is a trend for consanguineous marriages or a ‘founder effect’ in small populations in particular geographic areas because &
of a limited genetic pool. In spite of the prevalence being close to that of type 1 diabetes mellitus, familial hypercholesterolaemia is often underrecognized and undertreated [5]. The suspicion for a diagnosis of familial hypercholesterolaemia should come from nonspecialists for success in case finding. As routine screening is not available (unlike for some other inherited conditions), opportunistic screening by primary care physicians or cardiologists and other a Department of Metabolic Medicine, Clinical Biochemistry, Royal Free NHS Foundation Trust, London, UK and bDepartment of Clinical Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman
Correspondence to Dr Devaki Nair, BSc, MSc, FRCP, FRCPath, Consultant Chemical Pathologist and Clinical Lead for Lipids, Department of Metabolic Medicine and Clinical Biochemistry, Royal Free NHS Foundation Trust, London NW3 2QG, UK. E-mail: [email protected] Curr Opin Cardiol 2014, 29:381–388 DOI:10.1097/HCO.0000000000000083
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-cardiology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lipids and emerging risk factors
KEY POINTS Treatment of patients with familial hypercholesterolaemia is cost effective and prevents premature vascular disease. Cascade screening allows early diagnosis and early intervention of those with hypercholesterolaemia. If genetic testing is not available because of lack of resources, cascade testing should be carried out by cholesterol testing. Resources for cascade testing and genetic testing should be available as part of management of individuals with hypercholesterolaemia. New therapies such as PCSK9 inhibitors in addition to statin will help to get LDL-cholesterol levels to target in homozygous and severe heterozygous hypercholesterolaemia.
healthcare professionals is important. In HoFH, fatal cardiac events are common in their second or third decade if they remain untreated [6,7]. Most familial hypercholesterolaemia cases are caused by mutations in the gene for LDL-receptor (LDLR) or less commonly that for apolipoprotein B (apo B; a ligand for LDL-C) or proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that controls the number of LDLRs in the liver [4]. Some very rare forms of familial hypercholesterolaemia are caused by mutations in the LDLR adaptor pathway and have a recessive inheritance pattern. Several diagnostic criteria have been developed to improve the effectiveness of diagnosis of familial hypercholesterolaemia. However, lifestyle factors allied with high LDL-C concentrations attributed to polygenic hypercholesterolaemia (caused by small contributions from other LDL-C-raising genes) complicate the diagnosis of familial hypercholesterolaemia [8,9]. Treatment with statins and other LDL-C-lowering agents reduces vascular risk and improves prognosis for patients with familial hypercholesterolaemia to a level similar to (or even lower than) that of the general population [10,11]. Cost-effective primary prevention requires early diagnosis and treatment. In many patients with HeFH and in those with HoFH, available lipid-lowering strategies fail to get LDL-C levels to targets recommended by guidelines, especially in those with established vascular disease [12 ]. HoFH and severe HeFH [13] often also require LDL-C apheresis to reduce the concentration of LDL-C in the circulation. Recently, there has been significant progress in lowering LDL-C levels beyond the use of statins, ezetimibe, and bile acid &
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sequestrants (BASs). Agents such as PCSK9 inhibitors, oligonucleotide inhibitors of apo B-100 synthesis (mipomersen sodium) and microsomal triglyceride transfer protein (MTP) inhibitors (lomitapide) are being investigated (most are in phase III trials for the treatment of familial hypercholesterolaemia). These drugs will add to the much needed armamentarium used for the treatment of patients with HoFH or severe HeFH, and those intolerant to statins [14,15]. Globally, there are approximately 13 million people with a diagnosis of HeFH. In the United Kingdom, this number corresponds to 120 000 people [16]. The estimated frequency of HoFH is 1 in 860 000 in Germany [17]. Compound heterozygotes inherit two different mutant alleles whereas homozygotes have two identical mutant genes. In South African white Afrikaners, the estimated prevalence for HeFH is 1 in 100 and for HoFH it is 1 in 30 000 [18]. This effect, commonly known as the ‘founder effect,’ was introduced by the Dutch families that settled in Cape Province. Such a phenomenon is also seen in populations such as the French Canadians, Christian Lebanese, Tunisians, Indians, Icelanders and Finns [19]. Most other countries, such as Australia, China and countries in Europe, report a prevalence of 1 in 500. Familial hypercholesterolaemia is underdiagnosed, and there is a drive in many countries to increase awareness.
DIAGNOSTIC CRITERIA FOR FAMILIAL HYPERCHOLESTEROLAEMIA HoFH is characterized by exceptionally high LDL-C levels, higher than 13 mmol/l (500 mg/dl) in adults or >11 mmol/l (425 mg/dl) in a child, cutaneous and tendon xanthomata, valvular and supravalvular stenosis and accelerated atherosclerosis that manifests in the first two decades of life. Several diagnostic criteria have been developed: the Simon Broome criteria [20] in the United Kingdom, the MEDPED system in the USA [21] and the Dutch scoring system in the Netherlands [12 ]. A consistent, uniformly applied diagnostic or clinical definition is lacking. &
The Simon Broome criteria Definite HeFH is defined as total cholesterol > 6.7 mmol/l (250 mg/dl) or LDL-C above 4.0 mmol/l (150 mg/dl) in a child 7.5 mmol/l (300 mg/dl) or LDL-C above 4.9 mmol/l (190 mg/dl) in an adult together with tendon xanthomata in the individual, or in a first-degree relative (parent, sibling, and child), or in a second-degree relative (grandparent, uncle, and aunt) or a DNA-based evidence for familial Volume 29 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Familial hypercholesterolaemia Nair et al.
hypercholesterolaemia [20]. Possible HeFH is defined by cholesterol levels as above with family history of myocardial infarction: below age of 50 in a second-degree relative or below age 60 years in a first-degree relative or family history of raised cholesterol: >7.5 mmol/l (300 mg/dl) in adult firstdegree or second-degree relative or >6.7 mmol/l (250 mg/dl) in child or sibling under 16 years. There have been difficulties with inclusion of criteria such as tendon xanthomata, which could be part of later presentation. A positive family history for premature CVD that is part of the criteria may have multiple causes, including smoking, hypertension, low high-density lipoprotein cholesterol (HDL-C) levels or diabetes mellitus, and is not very specific to familial hypercholesterolaemia. The definition of positive family history as part of CVD prevention guidelines defines premature CVD as that in men
Familial hypercholesterolaemia Devaki R. Nair a, Mahtab Sharifi a, and Khalid Al-Rasadi b
Purpose of review Familial hypercholesterolaemia is associated with lifelong elevated cholesterol levels and is an important cause of premature coronary heart disease (CHD). This condition is often underdiagnosed and undertreated. Awareness of this condition is poor among nonlipid specialists. Treatment of elevated cholesterol levels with statins reduces the risk for CHD. The review will increase the awareness of this condition among nonspecialists. Recent findings Recently, several guidelines have been produced by different countries, but a unified approach to this global problem is addressed through a recent guideline facilitated by the Familial Hypercholesterolaemia Foundation. Although the widespread use of statins has been successful in reducing the risk for CHD in familial hypercholesterolaemia, there have been difficulties in getting to targets, especially in those with established vascular disease. New therapies such as mipomersen, a second-generation antisense oligonucleotide, microsomal triglyceride transfer protein inhibitors that decrease the synthesis of apolipoprotein B-containing lipoproteins and proprotein convertase subtilisin/kexin type 9 inhibitors hold promise in reducing cholesterol levels in those patients in whom low density lipoprotein cholesterol (LDL-C) reduction is required beyond the use of statins, especially in those with severe heterozygous familial hypercholesterolaemia or homozygous familial hypercholesterolaemia. Summary Increased awareness and wider availability of guidance to treat familial hypercholesterolaemia will improve management of familial hypercholesterolaemia. New therapies, if they become available after appropriate outcome studies, will reduce LDL-C levels in both homozygous familial hypercholesterolaemia and severe heterozygous familial hypercholesterolaemia, thus reducing the risk for premature CHD. Keywords familial hypercholesterolaemia, guidelines for familial hypercholesterolaemia, premature coronary heart disease
INTRODUCTION Familial hypercholesterolaemia is an autosomal dominant condition characterised by high low density lipoprotein cholesterol (LDL-C) concentration and a high risk for premature cardiovascular disease (CVD) [1 ,2]. The cumulative risk for fatal or nonfatal cardiac events is approximately 50% in men and 30% in women by 60 years of age in those with heterozygous familial hypercholesterolaemia (HeFH). In those under 40 years old, the relative risk for a nonfatal cardiac event is 100-fold greater than that for the general population [3]. The prevalence in Europe of HeFH is estimated to be 1 in 500 (and may be as common as 1 in 250), and for homozygous familial hypercholesterolaemia (HoFH) one in a million [4]. These figures may be higher in some populations, especially if there is a trend for consanguineous marriages or a ‘founder effect’ in small populations in particular geographic areas because &
of a limited genetic pool. In spite of the prevalence being close to that of type 1 diabetes mellitus, familial hypercholesterolaemia is often underrecognized and undertreated [5]. The suspicion for a diagnosis of familial hypercholesterolaemia should come from nonspecialists for success in case finding. As routine screening is not available (unlike for some other inherited conditions), opportunistic screening by primary care physicians or cardiologists and other a Department of Metabolic Medicine, Clinical Biochemistry, Royal Free NHS Foundation Trust, London, UK and bDepartment of Clinical Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman
Correspondence to Dr Devaki Nair, BSc, MSc, FRCP, FRCPath, Consultant Chemical Pathologist and Clinical Lead for Lipids, Department of Metabolic Medicine and Clinical Biochemistry, Royal Free NHS Foundation Trust, London NW3 2QG, UK. E-mail: [email protected] Curr Opin Cardiol 2014, 29:381–388 DOI:10.1097/HCO.0000000000000083
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-cardiology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lipids and emerging risk factors
KEY POINTS Treatment of patients with familial hypercholesterolaemia is cost effective and prevents premature vascular disease. Cascade screening allows early diagnosis and early intervention of those with hypercholesterolaemia. If genetic testing is not available because of lack of resources, cascade testing should be carried out by cholesterol testing. Resources for cascade testing and genetic testing should be available as part of management of individuals with hypercholesterolaemia. New therapies such as PCSK9 inhibitors in addition to statin will help to get LDL-cholesterol levels to target in homozygous and severe heterozygous hypercholesterolaemia.
healthcare professionals is important. In HoFH, fatal cardiac events are common in their second or third decade if they remain untreated [6,7]. Most familial hypercholesterolaemia cases are caused by mutations in the gene for LDL-receptor (LDLR) or less commonly that for apolipoprotein B (apo B; a ligand for LDL-C) or proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that controls the number of LDLRs in the liver [4]. Some very rare forms of familial hypercholesterolaemia are caused by mutations in the LDLR adaptor pathway and have a recessive inheritance pattern. Several diagnostic criteria have been developed to improve the effectiveness of diagnosis of familial hypercholesterolaemia. However, lifestyle factors allied with high LDL-C concentrations attributed to polygenic hypercholesterolaemia (caused by small contributions from other LDL-C-raising genes) complicate the diagnosis of familial hypercholesterolaemia [8,9]. Treatment with statins and other LDL-C-lowering agents reduces vascular risk and improves prognosis for patients with familial hypercholesterolaemia to a level similar to (or even lower than) that of the general population [10,11]. Cost-effective primary prevention requires early diagnosis and treatment. In many patients with HeFH and in those with HoFH, available lipid-lowering strategies fail to get LDL-C levels to targets recommended by guidelines, especially in those with established vascular disease [12 ]. HoFH and severe HeFH [13] often also require LDL-C apheresis to reduce the concentration of LDL-C in the circulation. Recently, there has been significant progress in lowering LDL-C levels beyond the use of statins, ezetimibe, and bile acid &
382
www.co-cardiology.com
sequestrants (BASs). Agents such as PCSK9 inhibitors, oligonucleotide inhibitors of apo B-100 synthesis (mipomersen sodium) and microsomal triglyceride transfer protein (MTP) inhibitors (lomitapide) are being investigated (most are in phase III trials for the treatment of familial hypercholesterolaemia). These drugs will add to the much needed armamentarium used for the treatment of patients with HoFH or severe HeFH, and those intolerant to statins [14,15]. Globally, there are approximately 13 million people with a diagnosis of HeFH. In the United Kingdom, this number corresponds to 120 000 people [16]. The estimated frequency of HoFH is 1 in 860 000 in Germany [17]. Compound heterozygotes inherit two different mutant alleles whereas homozygotes have two identical mutant genes. In South African white Afrikaners, the estimated prevalence for HeFH is 1 in 100 and for HoFH it is 1 in 30 000 [18]. This effect, commonly known as the ‘founder effect,’ was introduced by the Dutch families that settled in Cape Province. Such a phenomenon is also seen in populations such as the French Canadians, Christian Lebanese, Tunisians, Indians, Icelanders and Finns [19]. Most other countries, such as Australia, China and countries in Europe, report a prevalence of 1 in 500. Familial hypercholesterolaemia is underdiagnosed, and there is a drive in many countries to increase awareness.
DIAGNOSTIC CRITERIA FOR FAMILIAL HYPERCHOLESTEROLAEMIA HoFH is characterized by exceptionally high LDL-C levels, higher than 13 mmol/l (500 mg/dl) in adults or >11 mmol/l (425 mg/dl) in a child, cutaneous and tendon xanthomata, valvular and supravalvular stenosis and accelerated atherosclerosis that manifests in the first two decades of life. Several diagnostic criteria have been developed: the Simon Broome criteria [20] in the United Kingdom, the MEDPED system in the USA [21] and the Dutch scoring system in the Netherlands [12 ]. A consistent, uniformly applied diagnostic or clinical definition is lacking. &
The Simon Broome criteria Definite HeFH is defined as total cholesterol > 6.7 mmol/l (250 mg/dl) or LDL-C above 4.0 mmol/l (150 mg/dl) in a child 7.5 mmol/l (300 mg/dl) or LDL-C above 4.9 mmol/l (190 mg/dl) in an adult together with tendon xanthomata in the individual, or in a first-degree relative (parent, sibling, and child), or in a second-degree relative (grandparent, uncle, and aunt) or a DNA-based evidence for familial Volume 29 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Familial hypercholesterolaemia Nair et al.
hypercholesterolaemia [20]. Possible HeFH is defined by cholesterol levels as above with family history of myocardial infarction: below age of 50 in a second-degree relative or below age 60 years in a first-degree relative or family history of raised cholesterol: >7.5 mmol/l (300 mg/dl) in adult firstdegree or second-degree relative or >6.7 mmol/l (250 mg/dl) in child or sibling under 16 years. There have been difficulties with inclusion of criteria such as tendon xanthomata, which could be part of later presentation. A positive family history for premature CVD that is part of the criteria may have multiple causes, including smoking, hypertension, low high-density lipoprotein cholesterol (HDL-C) levels or diabetes mellitus, and is not very specific to familial hypercholesterolaemia. The definition of positive family history as part of CVD prevention guidelines defines premature CVD as that in men
