Familial Hypercholesterolemia

Q:I am a healthy 35-year-old man. I run regularly and eat a diet of mostly fish, chicken, and vegetables, yet I have elevated total cholesterol and my LDL (low-density lipoprotein) is extremely high. My doctor said I have familial hyper-cholesterolemia, inherited from my parents. What can I expect from this disorder, and how can I manage it other than by taking cholesterol-lowering drugs?

A: Familial hypercholesterolemia (FHC) is a common, inherited disorder characterized by elevated levels of total cholesterol and LDL. According to current medical wisdom, people with FHC have mutations in their gene coding for the LDL receptor protein.1 These individuals lack LDL receptors, which are molecules that can identify cholesterol. With fewer of these receptors, cells cannot remove cholesterol from the blood by normal means, causing cholesterol levels to rise.

FHC affects approximately one in every 500 people.2 It occurs much more frequently in some populations such as Afrikaners, Christian Lebanese, French Canadians, and Ashkenazi Jews, because a few members of these groups migrated and started new colonies, and because these “founder” populations married within the group.3,4 Such situations can lead to more frequent mutations in genes. Within these groups, a high proportion of individuals carry specific forms of genes responsible for the development of FHC. This condition is also strongly tied to certain environmental factors as well as to genetic influences.5

FHC is a health risk factor associated with an increased frequency of coronary heart disease. Among the worst outcomes are a heart attack suffered at an early age and premature death.6 The life expectancy of FHC patients is reduced by 15-30 years unless they undergo lipid-lowering therapy.7 This is why people with a family history of significantly elevated cholesterol, FHC, or heart disease should be specifically tested by their physician to determine whether they have FHC. Laboratory testing may show:

• total plasma cholesterol greater than 300 mg/dL (adult)
• total plasma cholesterol greater than 250 mg/dL (child)
• serum LDL greater than 200 mg/dL
• elevated triglycerides more than 200 mg/dL
• protein electrophoresis may show abnormal results
• studies of heart function such as a stress test may be abnormal
• special studies of patient cells (fibroblasts) may show decreased uptake of LDL cholesterol. LDL receptor gene defects can be identified with genetic testing.

Despite the investment of billions of dollars in research and the development of numerous cholesterol-lowering drugs, coronary heart disease is still a leading cause of death in developed countries. FHC is a major contributor to this deadly killer.

Conventional Treatment Options

If you are affected by FHC, your doctor will likely employ current standard medical treatment, which includes a diet low in saturated fat, cholesterol-lowering medications, daily exercise, weight control, and smoking cessation. These management options can help prevent complications such as lipid deposits in the skin, thickening of the Achilles tendon, atherosclerosis, and premature death.

In 1985, Michael Brown and Joseph Goldstein received the Nobel Prize in Physiology and Medicine for explaining the regulation of cholesterol metabolism.8 This led to the development of cholesterol-lowering statin drugs. Since the introduction of statins, FHC treatment has improved considerably. FHC patients frequently respond to these drugs, but they also quite often require additional treatment in combination with statins. New lipid-lowering agents are presently being developed for clinical use. The latest drug specifically targeted for FHC, Vytorin®, was approved by the FDA in July 2004. Vytorin® is a combination of ezetimibe, which lowers intestinal cholesterol absorption, and simvastatin, which inhibits cholesterol biosynthesis. Vytorin® thus acts via two different mechanisms to help lower cholesterol.

Unfortunately, there are many problems associated with the use of cholesterol-lowering drugs. First, the long-term safety of statin drugs in children with FHC has not yet been established. Because statins decrease the biosynthesis of cholesterol, which is a precursor to crucial hormones in the body, long-term exposure to these drugs might affect children’s growth and sexual development. For example, in one study, dehydroepiandrosterone sulfate (DHEA-S) levels were reduced relative to placebo in both boys and girls who were treated with statins.9 A small change in production of any hormones at a young age can lead to serious health problems in adult life.

Second, the long-term effects of ezetimibe on FHC cardiovascular morbidity and mortality are unknown.10 Third, statin drugs are associated with serious side effects, including poor quality of life, severe rhabdomyolysis (breakdown of muscle fibers), renal failure, and death.11-14 Statins can effectively lower cholesterol, providing the peace of mind that comes with a comfortably low level of cholesterol. But at what price? Many of the aforementioned health complaints may be related to low hormone levels that result from taking cholesterol-lowering drugs. The implication is that lowering elevated cholesterol levels in these patients has the effect of directly opposing (often very successfully) the body’s attempts to correct a more fundamental underlying hormone imbalance.

Other Treatment Options for FHC

In addition to the current standard medical practice cited above, there may be alternative approaches to the management of FHC to consider. While it has long been known that hormones in the body are produced from cholesterol, most doctors overlook the important fact that the body reacts to low hormone levels by increasing its cholesterol production. A similar situation occurs during pregnancy, when a woman’s need for more hormones for herself and her fetus results in significantly elevated cholesterol levels.15-17 No one would even think about treating a pregnant woman with drugs. The body naturally increases cholesterol production when there is an increased demand for hormones.

Elevated cholesterol is un-doubtedly a risk factor for heart disease. Science has not been able to answer the question of whether elevated cholesterol levels are a primary cause of coronary disease or a symptom of some other disease process. Correcting a disease’s symptoms rather than its underlying cause has never been a successful way to manage disease.

Despite significant success in lowering cholesterol levels through the use of statin medications, coronary heart disease remains a serious problem. This means that hypercholesterolemia, whether it occurs in young age or adult life, is not itself the cause of the coronary heart disease, but rather a symptom of an imbalance in the body that is causing the problem.

Cholesterol is the building block for important hormones such as pregnenolone, DHEA, testosterone, progesterone, estrogen, cortisol, and others. Elevated cholesterol should not be viewed as a primary disease, but rather as a symptom or consequence of hormonal imbalances.

Previous articles in Life Extension have addressed declining hormone levels as a primary cause of rising cholesterol levels with advancing age. In “Treating High Cholesterol by Replacing Hormones Lost to Aging” (Life Extension, September 2003), we suggested a new hypothesis of hypercholesterolemia. This hypothesis implies that elevated cholesterol serves as a compensatory mechanism for declining production of hormones. By proceeding from this theory, we have had success treating patients who have elevated cholesterol.

Is this a valid treatment approach for people with FHC? If we will agree that patients who suffer from FHC lack LDL receptors, what can be done? Practically nothing—except directly lowering cholesterol production or blocking cholesterol absorption from the intestinal tract. Based on clinical experience, however, we propose that the same mechanism that causes age-related cholesterol elevation is at work in FHC. Therefore, FHC should not be viewed as a primary disease, but rather as a secondary disorder associated chiefly with hormonal imbalances. We further believe that high cholesterol production is caused by low levels of steroid hormones. In other words, it is not familial hypercholesterolemia per se, but rather familial low hormone production that is responsible for this condition. If this hypothesis is correct, we would expect to see a lowering or normalization of both total cholesterol and LDL when a patient with FHC is treated using hormonorestoration.

In our experience with FHC, a medication-free approach produces better results than one using prescription drugs. This is done by observing the effect of hormones on the body and seeing how altering these levels to normal ranges can positively affect those suffering from FHC and high cholesterol in general. So far, the results have been very promising. In addition, this medication-free approach enables us to avoid the dangerous side effects that are so prevalent with prescription drug use.

We recommend that before people with FHC begin using powerful cholesterol-lowering drugs, they take a simple blood test to assess their hormone levels. Any deficiencies or suboptimal levels must be corrected to optimal youthful levels. In several patients with FHC, we restored cholesterol to normal levels after the patients initiated hormonorestorative therapy. Recently, two interesting cases of FHC were brought to our attention. Both cases illustrate the relationship between abnormal hormone levels and elevated cholesterol.

CASE # 1

A 38-year-old patient (5’11” tall and weighing 225 pounds) suffered from high total cholesterol of more than 500 mg/dL and high triglycerides of more than 1500 mg/dL. This man ate no red meat or eggs, and chose fat-free foods whenever possible. His wife understood that a statin medication would lower his lipid numbers, but she was concerned about possible side effects. His father, an active, full-time attorney in his seventies, also had very high cholesterol. While the patient’s family favored a natural approach of reducing cholesterol through supplementation and hormone modulation, the patient remained skeptical. The patient’s personal physician likewise was apprehensive about this treatment approach, as he was not familiar with using hormones to lower cholesterol. Furthermore, the physician did not understand why this patient would need hormones, since statins work well for treating FHC.

The patient became motivated to address his cholesterol problem after his ophthalmologist informed him that the blood vessels in his eyes resembled those of a man twice his age. This alarming news finally convinced him to take supplements, though he declined blood testing to examine his baseline hormone levels, despite our strong recommendation to do so. He started taking 50 mg of DHEA, 100 mg of pregnenolone, and 100 mg of coenzyme Q10 daily. After three months, his total cholesterol dropped to 350 mg/dL, but further progress was clearly necessary to achieve optimal health.

After ceasing to take the supplements regularly, the patient suffered a relapse and his cholesterol rose to 400 mg/dL. After this occurred, he increased his daily dose of pregnenolone to 300 mg and his dose of DHEA to 100 mg, and added to his regimen 600 mg of N-acetylcysteine, an antioxidant that supports healthy liver function. Eleven months later, his total cholesterol had dropped to 210 mg/dL and his triglycerides had decreased to 518 mg/dL. At this time, analysis of his hormone levels revealed the following results:

As you can see, the patient required a small modulation of his regimen because of his very low level of testosterone, a below-optimal level of pregnenolone, and high levels of estradiol and DHEA-sulfate. At this time, we suggested that the patient decrease his dose of DHEA, increase his dose of pregnenolone, and visit his doctor to obtain a prescription for micronized testosterone gel. We also advised him to take vitamin D3. Cholesterol serves as precursor for vitamin D3, and deficiency of this vitamin may be an additional cause of elevated cholesterol, just as a deficiency of hormones can lead to elevated cholesterol. We also suggested that he take saw palmetto and zinc to block the enzymes 5-alpha reductase and aromatase, respectively; 5-alpha reductase controls the conversion of testosterone to dihydrotestosterone (DHT), while aromatase controls the conversion of DHEA (through androstenedione) and testosterone to estradiol. Once the patient finally achieves optimal hormone levels, we anticipate a complete normalization and stabilization of his cholesterol problem.

CASE #2

The second patient, a 50-year-old man standing 5’ 7” tall and weighing 168 pounds, had used statin drugs since the age of 36. Before statin treatment, his total cholesterol was consistently over 350 mg/dL and his triglycerides were over 900 mg/dL. Even while using multiple statin drugs such as Zocor® and Crestor®, he was never able to lower his total cholesterol to below 240 mg/dL or his triglycerides to below 350 mg/dL.

The patient decided to implement a new approach. In addition to his statin medication, he began a daily regimen of 50 mg of DHEA, 100 mg of pregnenolone in the morning, and 4000 mg of EPA/DHA (eicosapentaenoic acid/docosahexaenoic acid). After eight months on this regimen, his total cholesterol had plummeted to 187 mg/dL and his triglycerides were down to 113 mg/dL. His C-reactive protein level was favorable at 0.37 mg/L. The patient said his doctor had asked him to stop using hormones because the doctor was concerned about the safety of DHEA and was unfamiliar with pregnenolone. Although he could not otherwise account for the patient’s dramatic drop in cholesterol, the doctor did not believe that the hormones were the cause.

Heeding his doctor’s request, the patient discontinued his use of DHEA, pregnenolone, and EPA/DHA for two weeks. A follow-up blood test at this time revealed that the patient’s total cholesterol and triglycerides had increased by 10 mg/dL and 20 mg/dL, respectively. This convinced the patient of the efficacy of the hormonorestorative therapy, and he resumed his previous protocol.

Our clinical experience shows that familial hypercholesterolemia could be considered familial low hormone production instead of familial high cholesterol. Such an approach may better define the problem and thus point the way to targeted treatments. Our clinical experience likewise demonstrates that hormonorestorative therapy can be a novel, effective, and inexpensive way to manage familial hypercholesterolemia without using cholesterol-lowering statin drugs.

As with all medical problems, please discuss the possibility of another treatment option for FHC with your physician.

Sergey A. Dzugan MD, PhD, was formerly chief of cardiovascular surgery at the Donetsk Regional Medical Center in Donetsk, Ukraine. Dr. Dzugan's current primary interests are anti-aging, biological therapy for cancer, cholesterol, and hormonal disorders.