Statins and Ulcerative Colitis


dr_duane_graveline_m.d._134By Duane Graveline, MD, MPH

Although this report has just come to my attention, it took place in 2002 so it hardly could be called news to the medical community, but what makes it so deserving of another look is that it was unique, a first of a kind and so very deadly.(Ref 1 and 2).

A 65 year old man placed on Pravachol who soon thereafter developed classic symptoms of ulcerative colitis. This condition promptly resolved after discontinuation of the statin only to re-appear several months later when Zocor was started.

This man was in extremely poor condition when he finally appeared at the hospital, the statin was stopped and emergency treatment started. His rapidly deteriorating condition resulted in the necessity for surgical removal of his colon, rectum and anus with his rapid demise thereafter.

The attending physician in attempting to discuss mechanisms of statin damage correctly stated that, “The mechanisms through which the statins cause diarrhea and colitis may relate to their non-lipid lowering effects.” Indeed, the so-called anti-inflammatory and immuno-modulatory properties of statins are those derived from inhibition of CoQ10 and dolichols as well as nuclear factor - kappa B and are many and varied.

The ultimate effect of CoQ10 and dolichol inhibition is mitochondrial DNA loss, which if sufficient, leads to cell loss and even organ deficiency. Inhibition of NF-kB results in benefit in inflammatory conditions and increased susceptibility to cancer with loss of immuno-resistance.  He correctly adds that, “Statins upregulate endothelial nitric oxide synthase and, as a consequence, increase the levels of nitric oxide in tissues. In addition, statins have been shown to stimulate the production of various cytokines, notably tumour necrosis factor-alpha, interleukin (IL)-B, and IL-8.”

What he is really saying here is that the statins in use today are far removed from the simple reductase inhibitors we thought we were getting when the statins first were introduced to the medical community. We were delighted in finally having a medicine that worked.

Statins blocked the single reductase step in the long stepwise chain of chemical reactions that finally led to cholesterol. It worked like magic – lowering cholesterol some fifty points in a few weeks in most people. In my case 10mg of Lipitor brought my 270 cholesterol down to 155 in just three weeks.

Little did we know then of the truth about this simple reductase inhibitor, for in blocking cholesterol, statins must inevitably block the synthesis of CoQ10 and dolichol. It is just as inevitable as night following day. This leads to dramatic changes in the cellular functions of most people.

Some of us have alternate pathways and are quite resistant to these adverse effects of statins. Doctors understand this. When you give a medicine to ten patients with the same condition only six of them will react as expected. Two will hyper react and two other will express no effect whatsoever. Doctors see this every day. Variation is the key.

Doctors could hardly be warned by the drug companies when they themselves did not know what to expect. This is what happened because of the pressure to market a potential billion dollar product. But Merck knew something was coming back in 1990 when they filed with the U.S. Patent Office for a combined Mevacor/CoQ10 pill because of, “the inflammation to come.” Yet when permission was granted they simply filed it away and never said a word to the medical community about these expected “inflammatory” reactions.

Long before Merck in the mid-seventies, while evolving the first statins, early researchers learned how critical CoQ10 and dolichols were to cellular functions. They showed that statin inhibition actually caused a hundred fold increase in reductase as cells desperately tried to protect themselves. You can imagine my surprise to learn only recently that the effect of statins drugs is to greatly enhance the output of the reductase enzyme, to amounts far higher than normal.

Ever since 1988, when I first prescribed lovastatin, I have been under the impression that statins work by reductase inhibition thereby blocking the mevalonate pathway. Now I find that during the time period 1973 to 1980, four researchers, Michael Brown, Joseph Goldstein, Jerry Faust and Akira Endo had already jointly discovered most of the control mechanisms at work in the mevalonate pathway.

Their earliest work published in the Journal of Biological Chemistry, 1973 revealed that compactin, the first reductase inhibitor to be conceived, actually increased reductase. Compactin, the first statin is also known as ML236B. Later work demonstrated that this increased reductase could not be suppressed by adding only cholesterol to cultured cells.  Additional non-cholesterol biochemicals like CoQ10, dolichols and mevalonate had to be added to accomplish this.

This was the first red flag, but it was ignored and by the time drug company management got through with it, only cholesterol mattered. Cholesterol was our greatest enemy so they knew they could focus just on that and simply ignore the non-cholesterol essentials.

At that time when, selling statins to a doctor, it was easy to focus on cholesterol, public health enemy number one. But just think if the drug reps had to tell the truth about statins. "Oh yeah, it blocks the synthesis of CoQ10 and dolichols in additon to cholesterol." It would not work. Some of us would have asked questions. So management said forget it and just focus on cholesterol.  The price we paid to be guinea pigs are the hundreds of thousands of adverse reactions being reported and, more importantly, being unreported. Being hidden and ignored.

It was Akira Endo who first coined the phrase “the cells must adapt or die” to describe this effect of compactin, the first statin, because cells need both cholesterol and non-cholesterol mevalonate-based products to grow and replicate. A logical interpretation of this excess reductase  response to reductase inhibition is that this enhancement of the reductase enzyme is an indicator of just how critical this biochemical stepping stone known as reductase is. The life of the cell is absolutely dependent upon it.

Back to the ulcerative colitis case with the attending physician trying to explain how a patient could go wrong so fast. Statins can do this. Statins interfere with the function of every cell in the body. This is how they work. Ordinarily they do not kill so rapidly. When he finally got to the hospital every cell in his body was desperately trying to survive. Statins had already overwhemed him. As Akira Endo said. “The cells must adapt or die.”

Ref 1: http://www.ncbi.nlm.nih.gov/pubmed/12151572

Ref 2: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1742344/pdf/v078p00286.pdf

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

September 2013
 


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