***The paper is now published. Read it here.***
In the latest issue of the Quarterly Review of Biology (Vol 86 Number 4, December 2011), in a paper titled "Multiple Sclerosis is Not a Disease of the Immune System," Dr Angelique Corthals argues that multiple sclerosis (MS) isn't a disease of the immune system: it is caused by faulty lipid metabolism.
The very basic précis of the paper: looking at MS as a metabolic disorder helps to explains many puzzling aspects of the disease. MS cases are on the rise as a direct consequence of a high-sugar, high-animal-fat diet. MS is similar in many ways to atherosclerosis.
This is huge. It is not an incremental improvement of what's known about MS, it's a paradigm shift. It will change the way MS is understood, researched, and treated.
Full disclosure: Angelique is a good friend of mine. I've seen every draft of this paper. It is not original research. It's an overview of what is known to be known. It takes what has been researched, reviewed and replicated and reassembles it into something utterly new: a jigsaw puzzle in which, for the first time, all the pieces fit. There are no pieces left out, none hammered in with brute force. It's brilliant. It's elegant, clean, and makes complete and utter sense.
At some point soon I'll write about how this makes me feel. But today I want to give you the gist of the paper without editorialising. (All mistakes are mine; nifty illustration and direct quotes are from Angelique.)
WHAT THE PAPER SAYS
The medical profession has believed for a long time that MS is a disease in which the body’s own immune defenses attack nerve tissue in the central nervous system. [For an overview of changing medical wisdom, see The Incredible Journey, courtesy Rocky Mountain MS Center.] The disease's main characteristic is inflammation, then scarring, of tissue called myelin which insulates the brain and spinal cord. Over time this scarring can lead to profound neuron damage.
Researchers have thought that the fault lies with a runaway immune system, but no one's been been able to explain what triggers the onset of the disease. They've linked genes, diet, pathogens, and vitamin D deficiency to MS, but evidence for these risk factors is oddly inconsistent and often contradictory. This frustrates researchers in their search for effective treatment.
"Each time a genetic risk factor shows a significant increase in MS in one population, it's been found to be unimportant in another. Pathogens like Epstein-Barr virus have been implicated, but that doesn’t explain why genetically similar populations with similar pathogen loads have drastically different rates of disease. The search for MS triggers in the context of autoimmunity simply hasn’t led to any unifying conclusions about the etiology of the disease."
Understanding MS as metabolic in origin rather than autoimmune begins to bring the disease and its causes into focus. "The new approach explains both the recent rise in incidence and all pathological, genetic, and environmental aspects of the disease."
In other words, this new understanding of MS will finally make it possible to find effective treatment--including preventative treatment.
Corthals believes that the primary cause of MS can be traced to transcription factors in cell nuclei that control the uptake, breakdown, and release of lipids (fats and similar compounds) throughout the body. When the lipid-metabolizing function of these receptors, known as peroxisome proliferator-activated receptors (PPARs), is disrupted, it can cause the accumulation of toxic lipids known as oxidized LDL, which form plaques on the affected tissues. The accumulation of plaque triggers an immune reaction, in part also regulated by the PPARs. With a failed inflammation control and the accumulation of oxLDL, the immune response runs amok and the toxic plaques leads to scarring of the tissue. The mechanism is essentially the same as atherosclerosis, in which PPARs' failure in heart cells leads to inflammation and an immune response in coronary arteries. "When lipid metabolism fails in the arteries, you get atherosclerosis. When it happens in the central nervous system, you get MS."
There are several risk factors for reduced PPAR function, including:
- a diet high in saturated fats and carbohydrates
- genetic predisposition
- environmental factors (such as poor exposure to sunlight or sources of vitamin D)
If the PPARs and the disruption of lipid homeostasis are the culprit in MS, it would explain why statin drugs, which are used to treat high cholesterol, have shown promise as an MS treatment. It would also explain why cases of the disease have been on the rise in recent decades. "In general people are increasing their intake of sugars and animal fats, which often leads to high LDL cholesterol. So we would expect to see higher rates of disease related to lipid metabolism—like heart disease and, in this case, MS."
It also sheds light on the vitamin D link. Vitamin D helps to lower LDL cholesterol, so it makes sense that vitamin D deficiency increases the likelihood of the disease—especially in the context of a high-fat/high-carbohydrates diet.
The lipid hypothesis also explains the inconsistent evidence for MS triggers. In many cases, Corthals says, having just one of the risk factors for reduced PPAR function isn’t enough to trigger a collapse of lipid metabolism. But more than one risk factor could cause problems. For example, a genetically weakened PPAR system on its own might not cause disease, but combining that with a poor diet can. Under these conditions, the body is "primed" for the onset of the disease, which is then triggered either by a pathogen (it can be any) or trauma, or even stress.
Finally, the lipid hypothesis also explains why MS is more prevalent in women.
"Men and women metabolize fats differently. In men, PPAR problems are more likely to occur in vascular tissue, which is why atherosclerosis is more prevalent in men. But because of the way women metabolize fat differently in relation to their reproductive role, their lipid metabolism is more likely to affect the production of myelin and the central nervous system, leading to the neurological equivalent of atherosclerosis. MS is more prevalent in women, just as atherosclerosis is more prevalent in men--but this framework excludes neither sex from developing the other disease."
Much more research is necessary to fully understand the role of PPARs in MS, but Corthals hopes that this new understanding of the disease could eventually lead to new treatments and prevention measures:
"This new framework makes a cure for MS closer than ever."
And that, dear reader, is the magic word: cure. For the first time, ever, I think there might one day be one. Even better, we might be able to prevent MS.
If you have questions--and I'm sure many of you do--please drop a comment here. Angelique has promised to answer as many as she can. I will, too. But please note: neither of us will give specific medical direction or advice. For one thing, I'm seriously not qualified. For another, there is no substitute for talking in person to your healthcare professional. I'm happy to share my opinion--I'm opinionated; it's my blog--but do not construe this as medical advice. Angelique will discuss her understanding of MS in general, particularly as it relates to this new paradigm. But she will not tell you what you should do. There will be no exceptions.
ETA: QRB is not yet live (sigh), so I've reverted the link to the forthcoming page. I'll update when this changes.
ETA2: This an emotional topic. I will be moderating comments here carefully. Please remember that neither Angelique nor I am making money from this. This blog post is a service. Don't even think of getting impolite or I'll delete your comment. Let's all play nicely.
ETA3: QRB informs us there's been a delay and the paper will go live on Friday. But I have a copy of the final document, the PDF that will be downloadable free in a couple of days. It's 25 pages of double-columned, densely argued fabulousness, with 9 pages of double-columned bibliography. It is solid. For those who know their PPARs from their peroxisomes and can't wait until Friday, email me.
ETA4: Comments on this post are now closed.