Familial Hypercholesterolemia – a Common Yet Life-Threatening Genetic Disorder
This article was originally published on HomeCareforYou.com.
You or someone you love might be harboring an undetected threat called Familial Hypercholesterolemia (FH). As genetic disorders go, FH is quite common. In fact, the condition occurs five times as frequently as Cystic Fibrosis. FH victims typically have severely elevated cholesterol; their disorder frequently remains undetected; and most patients develop vascular disease very early in life. These people often die from heart attacks in their forties and fifties. One consequence of the explosion in our understanding of genetics has been the discovery of more than 1600 genetic mishaps that can lead to FH. In the general population this disorder occurs in one out of every 500 people. Specific populations called founder groups (groups of people who are descendants of a genetically similar small population) such as French Canadians, Christian Lebanese, and South African Ashkenazi Jews have a prevalence of this malady that can be as high as one in sixty-seven people.
So what is FH and how does it harm so many?
In order to understand this ailment we must first review a few basic elements regarding cholesterol and its main transporter, LDL (Low Density Lipoprotein). Cholesterol is the building block for many key components in our body. LDL is a spherical lipoprotein particle that carries cholesterol. Think of it as a floating bubble that carries its freight— cholesterol and triglycerides—from one part of our body to another. This LDL “bubble” serves as a barrier “protecting” us from what would otherwise be the consequence of cholesterol floating freely in the blood. The result of that scenario would be instant death; free cholesterol would form razor-sharp crystals shredding anything in its path. LDL particles obviously provide a valuable function as our body’s dominant cholesterol transporters, but they have been dubbed the “bad cholesterol” because overly-abundant levels of these lipoproteins clearly lead to heart attacks and strokes. Thousands of studies have proved this; it is one of the few “facts” we have in modern medicine. As a result of our understanding of the detrimental consequences of high LDL, medications such as the statins have been created to lower LDL levels and in turn diminish our chances of experiencing a heart attack or stroke.
Lowering LDL with statins
Most of us know that the fundamental medication in cholesterol management is the statin. Statins work by blocking a critical enzyme in the multi-stepped process of cholesterol synthesis. This enzyme is present in every cell in the body. In response to the statin-induced cholesterol decline within our cells, affected cells deliver a greater number of LDL receptors to their surface. Think of receptors as adhesive-coated indentations in the cell membrane. These receptors capture the LDL “bubbles” as they float by in the blood. The receptor with its bonded LDL particle is then brought inside the cell. Within the cell, the cholesterol contained within the LDL particle can be utilized in any way the cell deems fit. For instance, it can be a building block for Vitamin D in the skin, bile acids in the liver, or testosterone in the testes. Once a cell has acquired enough cholesterol to serve its manufacturing needs, it stops overproducing LDL receptors. All cells engage in this process, but our liver is the organ that manufactures the majority of LDL receptors, thereby most meaningfully diminishing the content of LDL within our blood. To maintain a healthy balance of LDL within our bodies it is essential for our cells – particularly within our liver – to be able to produce LDL receptors, position them on their surface, and capture their prey—LDL particles.
The Malady of FH
Patients with Familial Hypercholesterolemia possess a genetic defect that disrupts their LDL receptors. In some cases the patient manufactures too few receptors; in others, the receptors themselves are defective. Even though they capture LDL, faulty receptors are unable to successfully bring their cargo into the cell. This defect results in a situation wherein the cell “effectively” lacks LDL receptors. There are two types of FH patients, those who have inherited one faulty gene from one parent (the common variety – 1 in 500) and those who have inherited one faulty gene from both parents (the extraordinarily rare form – 1 in 1,000,000). When an individual receives an abnormal gene from only one parent, he or she is known as heterozygous for the particular genetic flaw involved. An individual is homozygous for a disorder when both parents contribute abnormal genes. Because of the nature of the FH genetic defect, heterozygous individuals–those possessing only one genetic error from one parent–will experience the disorder, albeit in a less aggressive form than their homozygous counterparts. As this defect causes suboptimal LDL receptors, patients develop extraordinarily high LDL cholesterol levels. A typical heterozygous patient will have LDL cholesterol in the 200s. Homozygotes have LDL cholesterols over 500! So here is the problem. From conception on, FH patients’ bodies are bombarded with excess LDL cholesterol. Their arteries, tendons, eyes… everything is soaked in cholesterol. In contrast to patients who do not have this disorder, afflicted individuals have a markedly prolonged burden of high LDL. They bathe in cholesterol their entire life. That is why these individuals develop premature cardiovascular disease. In fact, patients with FH have a 12-fold higher risk of coronary artery disease compared with their own unaffected relatives. FH patients have a fifty percent mortality by the age of sixty if they are inadequately treated. And even more frightening, FH patients typically live their lives in the dark, undiagnosed and untreated. With- out being properly recognized, appropriate and life-saving care cannot possibly be rendered. Thus, our charge is crystal clear: Doctors must improve our ability to identify these patients early on in life and by so doing treat them appropriately and diminish their risk of dying young.
The FH patient
Let’s truly “look at” the patient with FH. In order to be able to recognize and appropriately treat these individuals, doctors and patients must be familiar with what this disorder looks like. First it’s critical to know that LDL cholesterol levels fluctuate throughout our lifetimes. We are born with our lowest levels, and after puberty LDL steadily rises throughout the rest of our lives. So pediatricians must appreciate that an LDL cholesterol of 160 might indicate the presence of FH, whereas in an adult this same LDL cholesterol level would be considered only moderately elevated. It is also important to understand that men and women have very different cholesterol levels. Until menopause, women have lower total cholesterol, LDL cholesterol, and triglyceride levels; and higher HDL cholesterol levels than men. Unfortunately, after menopause each of their lipid parameters deteriorates. Thus, physicians need to have a solid grasp of the influence that gender and age have on all lipid values (my lecture on this can be found at (http://aspconline.org/resources/ highlights.php). You can see that there is often great complexity in interpreting lipid and lipoprotein values; it is therefore important at times for patients to see lipid specialists in order to receive more refined therapy (To find a lipid specialist near you, visit www.lipid.org). We know what FH patients’ lipids look like, and we know that their vascular tree is severely diseased by an overabundance of LDL, but what other manifestations result from such high lifetime LDL levels? In addition to vascular disease, there are also disfiguring non-arterial consequences of FH. A life-time of markedly elevated LDL cholesterol can lead to an accumulation of fat in unusual parts of our bodies. Our tendons are often affected where fatty deposition can lead to palpable lumps called xanthomas. The Achilles tendon is a frequent target of this aberrant fat accumulation. Tendon xanthomas can easily be seen by the naked eye. Our palms can also be affected, with an abnormal yellowish discoloration in their creases called palmar xanthomas. Another area for physicians to focus their attention is our eyes. In the corner of the eye, adjacent to the nose, we can at times see yellowish deposits called xanthelasmas. In the eye itself, we sometimes see light-toned fatty deposits called corneal arcus. These tend to occur on the bottom and top of the cornea at the edge of the iris (the-colored part of the eye) because that is where the density of blood vessels is greatest. Seeing tendon and palmar xanthomas, or corneal arcus in patients under the age of forty-five, essentially confirms the diagnosis of FH.
Treatment Options
In 2011, initiating an FH call to action, the National Lipid Association released guide- lines to improve the identification and treatment of these patients. The NLA guidelines emphasize early detection; we now know that under appropriate circumstances very young children (even two years old in some cases!) should be screened. Once a patient has been diagnosed with FH, it is important not to stop there, but to perform “cascade” testing. This is a rigorous search of the patient’s relatives to determine who among them might also have the disease. Through proper cascade testing, doctors can discover many additional patients who would otherwise have been left untreated. Along with the National Lipid Association, other organizations such as the American Society for Preventive Cardiology and The FH Foundation are doing their part to raise FH awareness. Pharmaceuti- cal companies such as Genzyme and Aegerion are also help- ing out. Pharmaceutical companies frequently sponsor scientific educational conferences, enabling doctors to remain current with the ever-changing landscape of medical knowledge. They build websites devoted strictly to educating the lay public, allowing all people to more effectively become their own advocates. And of course they also create the medications, such as statins, that lower our risk of heart attack and stroke. In the case of FH, Gen- zyme has fashioned a novel medication, Mipomerson, in order to more effectively manage patients with extraordinarily high LDL levels. Aegerion has created Lomitapide another unique LDL-lowering agent. Other innovative agents are in the works. Those of us who specialize in the management of severe lipid disorders are thrilled to have access to ground-breaking medications that will hopefully make an even greater dent in the damage inflicted by FH. Finally, let’s examine the state-of-the-art management of FH individuals.
First and foremost, diet and exercise are always paramount in maintaining optimal cardiovascular health. For FH patients though, more aggressive treatment is always needed. To “get them to goal”, combination therapy is uniformly required, which means using a statin as the foundation and then adding two, three, or even four other medications. Novel agents such as Lomitapide (Aegerion) and Mipomerson (Genzyme) were recently FDA-approved for the treatment of severely afflicted FH patients. These medications represent a new and welcome addition to Lipidologists’ medical armamentarium. Even still, many of these patients require more aggressive interventions. One of the best modalities available is LDL-Apheresis. In a manner similar to dialysis (minus the fatigue and potential side-effects), patients are connected to a filtering machine through two IV lines. Blood is withdrawn from one IV, circulated through a series of filters, and returned to the body through the other IV. Typically the two-hour procedure is performed in an outpatient- setting once every other week. Each treatment results in a 60 percent to 80 percent reduction in LDL (other pro-atherogenic substances are also removed). Over the ensuing two weeks, the LDL rises steadily until it can be lowered once again with another treatment. Despite the fact that LDL gradually increases between treatments, studies have demonstrated a nearly 75 percent reduction in cardiovascular events when patients are treated with LDL-Apheresis. Thus, LDL-Apheresis is a viable option for difficult-to-treat heterozygotes and mandatory for all homozygotes. (To find a center near you, visit www.lipid. org) Familial Hypercholesterolemia is a frequently undiagnosed genetic disorder adversely affecting patients’ lipids and leading to premature heart attack, stroke, and death. A solid understanding of age and gender associated lipid fluctuations, physical signs of FH, and the nuances of cholesterol management is essential for doctors to diagnose and treat this disease. Somewhere between 600,000 and one million Americans suffer from FH. Consequently we must do our best to understand, manage, and perhaps most important of all, “spread the word” about this insidious but conquerable threat. It is a mission that can be accomplished only through the coordinated efforts of doctors, scientists, medical associations, industry, and patients themselves. Fortunately, this is what we find taking place today.
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