Andrea Jansen VanRensburg

Familial Hypercholesterolemia

Familial Hypercholesterolemia (FH) is an inherited genetic disease which results in high cholesterol levels in an individual (Pierce 2003) and occurs in approximately 1 in every 5 individuals (Fouchier et al. 2005).

Cholesterol is always portrayed in the media as a "bad thing", but in fact, it is a vital part of the human body. It is an important part of cell membranes, is involved in the synthesis of bile salts, many hormones (Pierce 2003), many steroids and is an important part of the nervous system (Saladin 2007). We get some cholesterol from the food we eat however 85% of our cholesterol is made by our own body (Saladin 2007). On average, an adult has over 200g of cholesterol in their body (Saladin 2007).

Cholesterol is carried to the cells in the body by lipoproteins (Saladin 2007). They are made up of a core of lipids (cholesterol and triglycerides) and surrounded by phospholipids and proteins (Pierce 2003). These lipoproteins are arranged into 4 categories depending on their density; chylomicrons, high-density lipoproteins (HDLs), low-density lipoproteins (LDLs) and very low-density lipoproteins (VLDLs) (Saladin 2007). The liver produces cholesterol according to the bodies needs, and compensates for dietary intake (Saladin 2007).VLDLs are produced in the liver and then circulate the body and distribute fatty acids to certain muscle and adipose tissues (Daniels et al. 2009). As the VLDL loses these substances it becomes an LDL (Daniels et al. 2009). The LDLs distribute the cholesterol to cells of the body which require it via an LDL receptor (Saladin 2007). Approximately 70% of the body's cholesterol is circulated by LDLs (Rader et al. 2003).

FH is an autosomal dominant disease which results in a mutation of the LDL receptor gene (LDLR) (Pierce 2003). Heterozygous individuals only have one gene mutation and homozygous individuals have mutations on both genes (Rader et al. 2003). The LDLR gene is located on chromosome 19 and hundreds of mutations have been found on this gene (Austin et al. 2004). These can be attributed to premature stop codons, single amino acid substitutions and mutations altering pre-mRNA splicing (Rabacchi et al. 2009). Also, in order for the LDL particle to bind with a receptor, a protein called apolipoprotein B (APOB) is needed (Fouchier et al. 2005). This is the structural protein for the LDL particle and if there is a mutation of the gene for this protein, it can also lead to high cholesterol levels (Fouchier et al. 2005). Patients with a mutation of the APOB gene are diagnosed with familial defective APOB however it is clinically the same as FH (Fouchier et al. 2005). Depending on the effect they have on the LDL receptor protein function, the LDLR mutations are classified into 5 classes (Austin et al. 2004).

The resulting problem of these mutations is that if the LDLR on cells do not recognize the LDLs then they aren't taken up and the levels of LDL in the blood increase (Fouchier et al. 2005).Unlike HDLs which extract cholesterol from tissues and deliver it back to the liver, LDLs tend to bind to the inner layer of arteries (Daniels et al. 2009) which can lead to atherosclerosis (Fouchier et al. 2005). Patients with FH have a heart attack because this build up of cholesterol (plaque) hardens and narrows the artery, the narrowing causes reduced flow of oxygen rich blood to the heart and other parts of the body (National Heart Lung and Blood Institute 2007).

Depending on how much LDLR receptor activity there is, patients with FH can be classified into two groups; Receptor-negative patients have less than 2% of normal LDLR activity and patients with 2-25% of normal LDLR are called receptor-defective (Rader et al. 2003). Studies show that receptor-negative patients are more likely to have cardiovascular disease, independent of other risk factors (Bertolini et al. 2000). This shows that some FH patients may not have heart attacks because their body can still maintain fairly low LDL levels as they still have some receptors working.

The most common treatment for patients with FH is the use of statins. They work by inhibiting the enzyme HMG-CoA reductase, which controls the rate at which cholesterol is made (Choumerianou & Dedoussis 2005). By reducing the rate at which cholesterol is produced, the liver responds to the decreased cholesterol level by expressing more LDL receptors which then clear up the LDL circulating the blood, and therefore decreasing LDL levels (Choumerianou & Dedoussis 2005). Another option is the use of bile sequestrants. They work by preventing the absorption of bile acids in the small intestine (Hopkins 2002). This causes an increase in the conversion of cholesterol to bile salts and decreases in liver cholesterol. Then again, to compensate for the low cholesterol level, the liver expresses more LDL receptors and the excess LDL in the blood is absorbed (Hopkins 2002).

In conjunction with the use of drugs the patient is also required to alter their diet to reduce the amount of cholesterol consumed; by reducing foods such as beef and pork and eliminating butter, egg yolks and other sources of oils and saturated fats (National Human Genome Research Insitite 2009). Patients with homozygous FH have a more severe case and may require the use of liver aphaeresis (the use of a continuous flow blood cell-separator which directly removes LDLs from the blood) or a liver transplant (Hopkins 2002).

Reference List

Austin, MA, Hutter, CM, Zimmern, RL, Humphries, SE 2004, 'Familial Hypercholesterolemia and Coronary Heart Disease: A HuGE Association Review', American Journal of Epidemiology, vol. 160, no. 5, pp. 421-429. Available from: Web of Science. [19th August 2009].

Bertolini, S, Cantafora, A, Averna, M, Cortese, C, Motti, C, Martini, S, Pes, G, Postiglione, A, Stefanutte, C, Blotta, I, Pisciotta, L, Rolleri, M, Langheim, S, Ghisellini, M, Rabbone, I, Calandra, S 2000, ' Clinical Expression of Familial Hypercholesterolemia in Clusters of Mutations of LDL Receptor Gene That Cause a Receptor-Defective or Receptor-Negative Phenotype', Journal of the American Heart Association, vol. 20, pp. 41-52. Available from: Web of Science. [27th August 2009].

Choumerianou, DM, Dedoussis, GVZ 2005, 'Familial hypercholesterolemia and respsone to statin therapy according to LDLR genetic background', Clin Chem Lab Med, vol. 43, pp. 793-801. Available from: MEDLINE. [29th August 2009].

Daniels, TF, Killinger, KM, Michal, JJ, Wright Jr., RW, Jiang, Z 2009, 'Lipoproteins, cholesterol homeostasis and cardiac health', International Journal of Biological Sciences, vol. 5, pp. 474-488. Available from: Web of Science. [19th August 2009].

Fouchier, SW, Rodenburg, J, Defesche, JC, Kastelein, JJP 2005, 'Management of hereditary dyslipidaemia; the paradigm of autosomal dominant hypercholesterolaemia', Europen Journal of Genetics, vol, 13, pp. 1247-1253. Available from: EMBASE. [August 21st 2009]

Hopkins, PN 2002, 'Familial Hypercholesterolemia-Improving treatment and meeting guidelines', International Journal of Cardiology, vol. 89, pp. 13-23. Available from: ScienceDirect. [29th August 2009].

National Heart Lung and Blood Institute 2007, What is Atherosclerosis. Available from: http://libguides.library.uwa.edu.au/content.php?pid=43218&sid=328596>. [30th August 2009].

National Human Genome Research Institute 2009, Learning about Familial Hypercholesterolemia, Available from: < http://www.genome.gov/25520184>. [27th August 2009].

Pierce, BA 2003, Genetics; A Conceptual Approach, 2nd edn, W.H. Freeman, New York

Rabacchi, C, Wunsch, A, Ghisellini, M, Marino, M, Pisciotta, L, Bertolini, S, Calandra, S 2009, 'An apparent inconsistency in parent to offspring transmission of point mutations of LDLR gene in Familial Hypercholesterolemia', Clinica Chimica Acta, vol. 406, pp. 75 - 80. Available from: ScienceDirect. [18th August 2009].

Rader, DJ, Cohen, J, Hobbs, HH 2003, 'Monogenic hypercholesterolemia; new insights in pathogenesis and treatment', The Journal of Clinical Investigation, vol. 111, no. 12, pp. 1795-1903. Available from: EMBASE. [30th August 2009].

Saladin, KS 2007, Anatomy and Physiology; The unity of form and function, 4th edn, McGraw-Hill, New York.

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