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Skin Cholesterol


Overview

In the past century, biologists portrayed the skin as a simple protective covering for the more important and complex internal organs. Over the past few decades, accumulated research has revealed the skin to be the largest and one of the more complex organs of the human body. Comprising approximately 17% of the total body weight and measuring almost 2 metres in surface area, the skin serves a number of vital functions.

Of course, the most important function is to protect the internal organs from microorganisms, toxins, and radiation. However, research has revealed that the skin is also directly involved in cholesterol metabolism. In fact, the skin contains approximately 11% of all the cholesterol found in the human body1, and cholesterol synthesis in the skin of mammals accounts for approximately 30% of total body cholesterol synthesis.

The main sources of Skin Cholesterol are epithelial steroidogenesis and cholesterol diffusion from circulation via LDL and SR-B1 receptors, making the epidermis a very active site of lipid synthesis. In fact, it is estimated that 10% - 15% of body cholesterol is removed by this cutaneous route, making this elimination channel second only to that involving the liver.

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Skin Cholesterol and its Link to Atherosclerosis and Coronary Artery Disease

In the 1970s, the French pathologist Bouissou reported that the skin and the aortic wall undergo very similar morphologic changes during aging and atherogenesis.2 One of the earliest studies involving Skin Cholesterol examined the relationship between Skin Cholesterol, aortic cholesterol and the extent of atherosclerosis in the aorta based on autopsy findings. This study confirmed the well-known fact that atherosclerotic changes in the aorta progress with age. However, and more importantly, the study also indicated that the changes observed in the aorta were paralleled by changes in cholesterol accumulation in the skin. The skin, like the blood vessels, accumulates cholesterol with age and multiple clinical studies have strongly established elevated Skin Cholesterol as a surrogate marker for atherosclerosis

For more information, please see Clinical Evidence.

Since the 1980s, increased serum cholesterol has been identified as a risk factor for atherosclerosis and coronary artery disease (CAD). But because cholesterol can be quantified in the skin, and given the large role skin plays in cholesterol metabolism, clinical thinking began to emerge surrounding how the measurement of Skin Cholesterol could provide a more accurate determination of lipid deposition, and thus atherosclerosis. What in turn emerged from this was the eventual development of a simple, fast and non-invasive method of cardiovascular risk determination that would come to be known as the PreVu® Non-Invasive Skin Cholesterol Point of Care (POC) Test - developed and advanced here in Canada.

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A New Paradigm of Understanding

The understanding of cholesterol and its relationship with CAD has evolved over the years. The early days of the serum cholesterol debate were focused around the importance of tracking Total Cholesterol in the blood. Over time though and through enhanced understanding of processes and outcomes, this thinking began to place great interpretative weight on blood serum fractions including HDL, LDL and their related ratios as a more important link to coronary disease.

The new paradigm that has been emerging over the last 10 years is that Skin Cholesterol - the cholesterol that is diffused and deposited into skin tissue as opposed to free circulating in the blood - can provide us with compelling new risk assessment information that is incremental and independent of traditional risk factors for CAD, including blood serum cholesterol.

stoplight cholesterol image

All of these progressive perspectives can provide the clinician with critical pieces of risk assessment data.

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PreVu Non-Invasive Skin Cholesterol Point of Care (POC) Test

Clinical evidence has conclusively demonstrated that high levels of Skin Cholesterol deposits are strongly associated with significant atherosclerosis and coronary artery disease as measured by treadmill stress test, angiography, carotid intima-media thickness/plaque, coronary calcium, inflammatory markers of vascular disease, previous Myocardial Infarctions and Framingham risk score.

Since 1999 there have been multiple studies, publications, clinical posters and scientific presentations related to Skin Cholesterol and the PreVu technology developed to measure it, that have been conducted and submitted by acclaimed researchers from institutions including The University of Wisconsin, School of Medicine and Public Health; The Cleveland Clinic Foundation, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Bayview Medical Center; The Atherosclerosis Imaging Research Program, Department of Medicine, Section of Cardiovascular Medicine, University of Wisconsin Medical School; and the University of Pennsylvania, Department of Experimental Therapeutics.

Much of this clinical data has been published in prestigious peer reviewed journals that include The American Journal of Cardiology; The American Heart Journal; Atherosclerosis; and Clinical Chemistry, while corresponding presentations have been made at some of the most important conferences and meetings in the clinical world including the Annual American Association of Clinical Chemistry Meeting; the American Heart Association Scientific Sessions; the Canadian Cardiovascular Congress; the Annual Scientific Session of the American College of Cardiology; the Endocrine Society Annual Meeting; and the American Heart Association Conference on Arteriosclerosis, Thrombosis and Vascular Biology.

For more information, please see Clinical Evidence.

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PreVu for General Screening and Risk Assessment

The PreVu POC Test has been developed to measure Skin Cholesterol as an important new biomarker for CAD and can assist healthcare professionals in the earlier detection and primary prevention of this #1 killer of Canadians.

It has been designed to serve as a general population screen out in the community and as a first step towards a global risk evaluation process for CAD, helping to identify those at hidden, high levels of risk who could benefit from more intensive primary prevention measures and to provide all those tested with a tipping point to better understanding their overall level of risk of CAD.

The PreVu POC Test is completely painless, non-invasive, involves no blood draw or needles, requires no overnight fasting and involves no handling of potentially hazardous biomaterials. It is conducted on the palm of the hand in less than 5 minutes with results being immediately available, facilitating point of care consultation within the clinic or a next steps discussion out in the community.

Identifying patients at high, hidden levels of risk and getting them into the global risk assessment stream for more comprehensive evaluation, is a responsive strategy to recent advances in research that have identified the value of aggressiveness in primary prevention.

Regardless of where a patient may encounter the PreVu POC Test - out in the community or in their doctor's office - the end goal is the same; to generate increased opportunities for healthcare professionals to conduct global CAD risk assessments on those in need, followed by primary prevention as may be required and best determined by your experience and expertise, to guard against that critical first coronary event.

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Basic Skin Biology: The Skin as Barrier

The skin is composed of two basic components - the epidermis and the dermis. The epidermis is a stratified squamous epithelium, and the underlying dermis is a loose connective tissue. The epidermis is avascular and acquires nutrients from the rich capillary network of the papillary dermis. The principal role of the skin is to protect the body against harmful agents and water loss. The epidermis and its associated lipids are central to preventing the rapid absorption or evaporation of water at the skin surface, in addition to controlling the diffusion of both hydrophobic and hydrophilic substances through the skin barrier. Skin lipids are a component of this external barrier that is essential to terrestrial life. In addition, the presence of lipids in the skin makes the skin one of the most important components of lipid metabolism in the body. Cutaneous lipid levels reflect several processes: an increase in the tissue pool of this sterol associated with normal aging (cholesterolosis); a genetically determined level of intracellular cholesterol metabolism designed to maintain the permeability barrier; and an effect of the blood plasma cholesterol level.

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Basic Skin Morphology and Lipid Physiology

The epidermis is comprised of five dynamic layers, which are, from deep to superficial: stratum germinativum (basal), stratum spinosum (prickle cell), stratum granulosum (granular), stratum lucidum (clear), and stratum corneu (horny) (Figure 1).

Figure 1: Schematic drawing of the basic structure of the skin

Skin Structure

The horny layer is in direct contact with the external environment. Skin varies in thickness over the body. In the palmar region, where the skin cholesterol test is performed, the thickness can be up to 0.8 mm. The main barrier of the skin resides in the uppermost layer - the stratum corneum. During the process of keratinization, basal cells convert into keratin-filled horny scales, which are eventually shed into the environment, causing a renewal of the horny layer every 3 to 13 days; however, it was discovered in the 1970s that the barrier function of the skin is also highly dependent on the presence of lipids, namely ceramides, free fatty acids, and notably nonesterified cholesterol. These lipids are predominantly present in the extracellular matrix between the cornified cells, and are thought to resemble the mortar in a bricks and mortar analogy (Figure 2).

Figure 2: Schematic diagram of stratum corneum "bricks and mortar" model

Bricks and Mortar

The intracellular matrix lipids take the form of broad lamellar bilayers, which originate from small ovoid organelles synthesized in the stratum spinosum and granulosum.

While epidermal cells actively synthesize cholesterol, they also take up lipids from the circulation via low-density lipoprotein (LDL) and Scavenger Receptor class B type I (SRBI) receptors, both of which are predominantly in the basal layer. The expression of LDL receptor mRNA is regulated by barrier requirements. SR-BI receptors mediate the selective uptake of cholesterol esters from circulating high-density lipoprotein. The expression of this receptor is regulated by cellular cholesterol requirements, suggesting that it also plays a role in keratinocyte cholesterol homeostasis, especially during membrane barrier disruption. It is postulated that these receptors coordinately mediate the uptake of lipids from the circulation; however, the relative importance of local lipid synthesis versus extracutaneous lipid uptake in skin cholesterol metabolism is still debated.

The epidermis is a very active site of lipid synthesis. It is estimated that 10% to 15% of body cholesterol is removed by this cutaneous route, making this elimination route second only to that involving the liver. This fact is significant because, given the large role that the skin plays in cholesterol metabolism, measuring skin cholesterol may provide a more accurate determination of lipid disposition, and thus atherosclerosis.

As a result, the PreVu Non-Invasive Skin Cholesterol Point of Care (POC) Test, which measures skin cholesterol, is an important advance in the further risk assessment of cardiovascular disease.

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Further Reading

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References

  1. Sabine, JR (1977) Cholesterol, New York: Marcel Dekkar
  2. Bouissou H, Pieraggi MT, Julian M, et al. Identifying arteriosclerosis and aortic atheromatosis by skin biopsy. Atherosclerosis 1974;19(3):449-58.
  3. Sprecher DL, Goodman SG, Kannampuzha P, et al. Skin tissue cholesterol (Skin Tc) is related to angiographically-defined cardiovascular disease. Atherosclerosis 2003;171:255-58.