History

Fact Explanation
Retrosternal chest pain. Due to coronary atherosclerosis causing angina. [1,2]
Calf and or thigh pain while walking which is relieved by rest. Due to peripheral Vascular Disease. [3]
Paralysis, slurring of speech, deviation of mouth or other neurological deficit. Due to cerebrovascular disease. [4]
Syncopal attacks. Due to aortic stenosis. [2]
Family history of significant hypercholesterolaemia and premature coronary heart disease. Because this is inherited in autosomal dominant manner. [5]
References
  1. ROBINSON JG. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care Pharm [online] 2013 Mar, 19(2):139-49 [viewed 15 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23461430
  2. BELL DA, HOOPER AJ, WATTS GF, BURNETT JR. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia Vasc Health Risk Manag [online] 2012:651-659 [viewed 15 August 2014] Available from: doi:10.2147/VHRM.S28581
  3. KROON A. A., AJUBI N., ASTEN W. N. J. C., STALENHOEF A. F. H.. The prevalence of peripheral vascular disease in familial hypercholesterolaemia. [online] 1995 November, 238(5):451-459 [viewed 17 August 2014] Available from: doi:10.1111/j.1365-2796.1995.tb01223.x
  4. HUTTER C. M.. Familial Hypercholesterolemia, Peripheral Arterial Disease, and Stroke: A HuGE Minireview. American Journal of Epidemiology [online] 2004 September, 160(5):430-435 [viewed 17 August 2014] Available from: doi:10.1093/aje/kwh238
  5. SOUTAR ANNE K, NAOUMOVA ROSSI P. Mechanisms of Disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med [online] 2007 April, 4(4):214-225 [viewed 17 August 2014] Available from: doi:10.1038/ncpcardio0836

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. [1]
Xanthelasma Due to fat deposition around eyes but this is not pathognomonic of familial hypercholesterolaemia. [2]
Premature corneal arcus Corneal arcus is a common finding in elderly people. But presence of this in young people can direct towards familial hypercholesterolaemia. [2]
Ejection systolic murmur Due to aortic stenosis. [3]
Diminished lower limb pulses, low ankle brachial pressure index (ABPI) and/or evidence of chronic arterial insufficiency. Due to associated peripheral vascular disease. [4]
References
  1. TERASAKI FUMIO, MORITA HIDEAKI, HARADA-SHIBA MARIKO, OHTA NAOTAKA, OTSUKA KAORU, NOGI SHINPEI, MIYAMURA MASATOSHI, SUZUKI SHUJI, ITO TAKAHIDE, SHIMOMURA HIROAKI, KATSUMATA TAKAHIRO, MIYAMOTO YOSHIHIRO, ISHIZAKA NOBUKAZU. Familial Hypercholesterolemia with Multiple Large Tendinous Xanthomas and Advanced Coronary Artery Atherosclerosis. Intern. Med. [online] 2013 December, 52(5):577-581 [viewed 17 August 2014] Available from: doi:10.2169/internalmedicine.52.8522
  2. WINDER A. F.. Relationship between corneal arcus and hyperlipidaemia is clarified by studies in familial hypercholesterolaemia.. British Journal of Ophthalmology [online] 1983 December, 67(12):789-794 [viewed 17 August 2014] Available from: doi:10.1136/bjo.67.12.789
  3. BELL DA, HOOPER AJ, WATTS GF, BURNETT JR. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia Vasc Health Risk Manag [online] 2012:651-659 [viewed 15 August 2014] Available from: doi:10.2147/VHRM.S28581
  4. KROON A. A., AJUBI N., ASTEN W. N. J. C., STALENHOEF A. F. H.. The prevalence of peripheral vascular disease in familial hypercholesterolaemia. [online] 1995 November, 238(5):451-459 [viewed 17 August 2014] Available from: doi:10.1111/j.1365-2796.1995.tb01223.x

Differential Diagnoses

Fact Explanation
Dysbetahyperlipoproteinemia (type III hyperlipidemia) This may present with xanthomas; caused by biallelic pathogenic variants (E2/E2) in APOE, the gene encoding apolipoprotein E. Mode of inheritance is autosomal recessive. [1,2]
27-hydroxylase deficiency (cerebrotendonous xanthomatosis) This is characterized by xanthomas. Distinguishing features are normal LDL cholesterol (LDL-C) levels and the presence of dementia, ataxia, and cataracts. Inheritance is autosomal recessive. [1]
Homozygous autosomal recessive hypercholesterolemia This is caused by biallelic pathogenic variants in LDLRAP1. Persons with biallelic pathogenic variants have LDL-C >400 mg/dL (>10 mmol/L), whereas heterozygotes have normal LDL-C levels. [1]
Sitosterolemia (Phytosterolemia) This is distinguished by normal or only mildly elevated LDL-C levels. Inheritance is autosomal recessive. [1]
References
  1. Youngblom E, Knowles JW. Familial Hypercholesterolemia. 2014 Jan 2. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK174884
  2. FUNG M, HILL J, COOK D, FROHLICH J. Case series of type III hyperlipoproteinemia in children BMJ Case Rep [online] :bcr0220113895 [viewed 17 August 2014] Available from: doi:10.1136/bcr.02.2011.3895

Investigations - for 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. [1,2]
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. [3]
Fasting blood sugar/ HbA1c To exclude hypercholesterolaemia secondary to diabetes mellitus. [3]
Thyroid profile To exclude hypercholesterolaemia secondary to hypothyroidism. [3]
References
  1. WILLIAMS ROGER R., HUNT STEVEN C., SCHUMACHER M.CATHERINE, HEGELE ROBERT A., LEPPERT MARK F., LUDWIG ERWIN H., HOPKINS PAUL N.. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. The American Journal of Cardiology [online] 1993 July, 72(2):171-176 [viewed 18 August 2014] Available from: doi:10.1016/0002-9149(93)90155-6
  2. BELL DA, HOOPER AJ, WATTS GF, BURNETT JR. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia Vasc Health Risk Manag [online] 2012:651-659 [viewed 15 August 2014] Available from: doi:10.2147/VHRM.S28581
  3. Youngblom E, Knowles JW. Familial Hypercholesterolemia. 2014 Jan 2. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK174884

Investigations - Fitness for Management

Fact Explanation
Vascular imaging To measure carotid intima medial thickness to direct treatment decisions in children.
Echocardiogram To exclude aortic stenosis.
References
  1. Youngblom E, Knowles JW. Familial Hypercholesterolemia. 2014 Jan 2. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK174884

Investigations - Screening/Staging

Fact Explanation
Lipid profile Screening family members of people with familial hypercholesterolaemia is the most cost effective option for detecting cases across the whole population. [1]
References
  1. MARKS D.. Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia. [online] 2002 June, 324(7349):1303-1303 [viewed 18 August 2014] Available from: doi:10.1136/bmj.324.7349.1303

Management - General Measures

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. [1,2]
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. [1,2]
Blood pressure should be treated to 140/90mmHg (or 130/80 mm Hg in those with diabetes mellitus). To reduce Coronary Heart Disease risk. [1,2]
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. [1,2]
References
  1. Youngblom E, Knowles JW. Familial Hypercholesterolemia. 2014 Jan 2. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK174884
  2. ROBINSON JG. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care Pharm [online] 2013 Mar, 19(2):139-49 [viewed 18 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23461430

Management - Specific Treatments

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. [1,2]
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. [3]
Cholesterol absorption inhibitors (ezetimibe) Reduces Cholesterol absorption; Increases LDLR activity. [1]
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. [3]
Bile acid sequestrants (cholestyramine, colesevelam) Reduces Bile acid re-absorption; Increases LDLR activity. [1,2]
Stanol esters Reduces Cholesterol absorption; Increases LDLR activity. [1,2]
Nicotinic acid Reduces VLDL synthesis. [1,2]
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. [1,3]
References
  1. Youngblom E, Knowles JW. Familial Hypercholesterolemia. 2014 Jan 2. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK174884
  2. ROBINSON JG. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care Pharm [online] 2013 Mar, 19(2):139-49 [viewed 18 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23461430
  3. BELL DA, HOOPER AJ, WATTS GF, BURNETT JR. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia Vasc Health Risk Manag [online] 2012:651-659 [viewed 15 August 2014] Available from: doi:10.2147/VHRM.S28581