Familial hypercholesterolaemia - Clinicals, Diagnosis, and Management

Endocrinology, Metabolism and Nutrition

Clinicals - History

Fact Explanation
Retrosternal chest pain. Due to coronary atherosclerosis causing angina. Retrosternal chest pain.
Due to coronary atherosclerosis causing angina.
Calf and or thigh pain while walking which is relieved by rest. Due to peripheral Vascular Disease. Calf and or thigh pain while walking which is relieved by rest.
Due to peripheral Vascular Disease.
Paralysis, slurring of speech, deviation of mouth or other neurological deficit. Due to cerebrovascular disease. Paralysis, slurring of speech, deviation of mouth or other neurological deficit.
Due to cerebrovascular disease.
Syncopal attacks. Due to aortic stenosis. Syncopal attacks.
Due to aortic stenosis.
Family history of significant hypercholesterolaemia and premature coronary heart disease. Because this is inherited in autosomal dominant manner. Family history of significant hypercholesterolaemia and premature coronary heart disease.
Because this is inherited in autosomal dominant manner.

Clinicals - Examination

Fact Explanation
Tendinous xanthomas Due to deposition of cholesterol (cholesterol clefts) and diffuse sheets of foamy cells (xanthoma cells) interspersed with inflammatory cells within fibrous tissue. Tendinous xanthomas
Due to deposition of cholesterol (cholesterol clefts) and diffuse sheets of foamy cells (xanthoma cells) interspersed with inflammatory cells within fibrous tissue.
Xanthelasma Due to fat deposition around eyes but this is not pathognomonic of familial hypercholesterolaemia. Xanthelasma
Due to fat deposition around eyes but this is not pathognomonic of familial hypercholesterolaemia.
Premature corneal arcus Corneal arcus is a common finding in elderly people. But presence of this in young people can direct towards familial hypercholesterolaemia. Premature corneal arcus
Corneal arcus is a common finding in elderly people. But presence of this in young people can direct towards familial hypercholesterolaemia.
Ejection systolic murmur Due to aortic stenosis. Ejection systolic murmur
Due to aortic stenosis.
Diminished lower limb pulses, low ankle brachial pressure index (ABPI) and/or evidence of chronic arterial insufficiency. Due to associated peripheral vascular disease. Diminished lower limb pulses, low ankle brachial pressure index (ABPI) and/or evidence of chronic arterial insufficiency.
Due to associated peripheral vascular disease.

Investigations - Diagnosis

Fact Explanation
Lipid profile This is a part of most diagnostic criteria. There are different total cholesterol cut-off values for the general population and family members of diagnosed patients. However some criteria define FH based on plasma LDL levels. Lipid profile
This is a part of most diagnostic criteria. There are different total cholesterol cut-off values for the general population and family members of diagnosed patients. However some criteria define FH based on plasma LDL levels.
Genetic testing Genetic testing most commonly involves the three genes LDLR, APOB, and PCSK9, as mutation of one of these genes accounts for approximately 60%-80% of FH. Genetic testing
Genetic testing most commonly involves the three genes LDLR, APOB, and PCSK9, as mutation of one of these genes accounts for approximately 60%-80% of FH.
Fasting blood sugar/ HbA1c To exclude hypercholesterolaemia secondary to diabetes mellitus. Fasting blood sugar/ HbA1c
To exclude hypercholesterolaemia secondary to diabetes mellitus.
Thyroid profile To exclude hypercholesterolaemia secondary to hypothyroidism. Thyroid profile
To exclude hypercholesterolaemia secondary to hypothyroidism.

Investigations - Management

Fact Explanation
Vascular imaging To measure carotid intima medial thickness to direct treatment decisions in children. Vascular imaging
To measure carotid intima medial thickness to direct treatment decisions in children.
Echocardiogram To exclude aortic stenosis. Echocardiogram
To exclude aortic stenosis.
Lipid profile Screening family members of people with familial hypercholesterolaemia is the most cost effective option for detecting cases across the whole population. Lipid profile
Screening family members of people with familial hypercholesterolaemia is the most cost effective option for detecting cases across the whole population.

Management - Supportive

Fact Explanation
Risk factors (e.g., smoking, diabetes mellitus, hypertension) are the same in FH as in the general population; aggressive management is required with special attention to smoking cessation. To reduce Coronary Heart Disease risk. Risk factors (e.g., smoking, diabetes mellitus, hypertension) are the same in FH as in the general population; aggressive management is required with special attention to smoking cessation.
To reduce Coronary Heart Disease risk.
Regular physical activity, a healthy diet (reduce saturated fat intake, increase intake of soluble fiber to 10-20 g/day), and weight control should be emphasized. To reduce Coronary Heart Disease risk. Regular physical activity, a healthy diet (reduce saturated fat intake, increase intake of soluble fiber to 10-20 g/day), and weight control should be emphasized.
To reduce Coronary Heart Disease risk.
Blood pressure should be treated to 140/90mmHg (or 130/80 mm Hg in those with diabetes mellitus). To reduce Coronary Heart Disease risk. Blood pressure should be treated to 140/90mmHg (or 130/80 mm Hg in those with diabetes mellitus).
To reduce Coronary Heart Disease risk.
Low-dose aspirin (75-81 mg/day) should be considered in those at high risk for CHD or stroke. To reduce Coronary Heart Disease risk and risk of cerebro vascular accidents. Low-dose aspirin (75-81 mg/day) should be considered in those at high risk for CHD or stroke.
To reduce Coronary Heart Disease risk and risk of cerebro vascular accidents.

Management - Specific

Fact Explanation
Medical therapy In persons with FH without any of the CHD risk factors, intensification of drug therapy should be strongly considered if 50% reduction in LDL-C is not achieved after six months on maximum statin therapy. For adults, some guidelines call for intensification of treatment if the goal LDL-C of <100 mg/dL (<2.6 mmol/L) is not achieved.

The lipid-lowering therapy should initially be statin-based with titration of doses every few months in order to use the highest tolerated dose of a potent statin, followed by addition of other drugs if the targeted LDL-C level is not achieved.

Treatment options for intensification of therapy or for those intolerant of statins include: ezetimibe, niacin, and bile acid sequestrants.

The potential benefit of multi-drug regimens should be weighed against the increased cost and potential for adverse effects and decreased adherence.
Medical therapy
In persons with FH without any of the CHD risk factors, intensification of drug therapy should be strongly considered if 50% reduction in LDL-C is not achieved after six months on maximum statin therapy. For adults, some guidelines call for intensification of treatment if the goal LDL-C of <100 mg/dL (<2.6 mmol/L) is not achieved.

The lipid-lowering therapy should initially be statin-based with titration of doses every few months in order to use the highest tolerated dose of a potent statin, followed by addition of other drugs if the targeted LDL-C level is not achieved.

Treatment options for intensification of therapy or for those intolerant of statins include: ezetimibe, niacin, and bile acid sequestrants.

The potential benefit of multi-drug regimens should be weighed against the increased cost and potential for adverse effects and decreased adherence.
Mipomersen This is a second-generation antisense oligonucleotide (ASO), which is administered by subcutaneous injection in a formulation with 0.9% sodium chloride and targets apoB-100 mRNA in the liver. Mipomersen
This is a second-generation antisense oligonucleotide (ASO), which is administered by subcutaneous injection in a formulation with 0.9% sodium chloride and targets apoB-100 mRNA in the liver.
Cholesterol absorption inhibitors (ezetimibe) Reduces Cholesterol absorption; Increases LDLR activity. Cholesterol absorption inhibitors (ezetimibe)
Reduces Cholesterol absorption; Increases LDLR activity.
Statins Atorvastatin 10 mg-80 mg Fluvastatin 80 mg Lovastatin 40-80 mg Pitavastatin 2-4 mg Pravastatin 40-80 mg Rosuvastatin 5-40 mg Simvastatin 20-40 mg 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (statins) are by far the most common and effective drugs with which to treat FH. However, statins require some residual LDL receptor function, thus they are not effective in receptor-negative homozygous FH. Statins Atorvastatin 10 mg-80 mg Fluvastatin 80 mg Lovastatin 40-80 mg Pitavastatin 2-4 mg Pravastatin 40-80 mg Rosuvastatin 5-40 mg Simvastatin 20-40 mg
3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (statins) are by far the most common and effective drugs with which to treat FH. However, statins require some residual LDL receptor function, thus they are not effective in receptor-negative homozygous FH.
Bile acid sequestrants (cholestyramine, colesevelam) Reduces Bile acid re-absorption; Increases LDLR activity. Bile acid sequestrants (cholestyramine, colesevelam)
Reduces Bile acid re-absorption; Increases LDLR activity.
Stanol esters Reduces Cholesterol absorption; Increases LDLR activity. Stanol esters
Reduces Cholesterol absorption; Increases LDLR activity.
Nicotinic acid Reduces VLDL synthesis. Nicotinic acid
Reduces VLDL synthesis.
Lomitapide Lomitapide is a small-molecule MTTP inhibitor designed as an oral, once-daily treatment for homozygous FH. It reduces microsomal triglyceride transfer protein activity ; inhibition of LDL production. Lomitapide
Lomitapide is a small-molecule MTTP inhibitor designed as an oral, once-daily treatment for homozygous FH. It reduces microsomal triglyceride transfer protein activity ; inhibition of LDL production.

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