1. It logically follows that a reduction in the quantity of neurotoxins would reduce, minimize or possibly prevent the further progression of loss of additional muscle strength in patients afflicted with ALS.
2. Elimination or prevention of additional hepatic generated neurotoxins would minimize or totally prevent further progression of the loss of muscle strength. These patients would tend to have a more normal life expectancy.
The most certain method of permanently preventing further production of hepatic generated neurotoxins would be to do a liver transplant (replacement). The probability of second liver producing similar neurotoxins is approximately one in 450,000 based on the current estimated incidence of ALS in the USA in 2016. If only a single patient is demonstrated is have total lack of progression of the loss of additional muscle strength following a liver transplant, the basic premise of the liver brain theory will have been validated.
Jan 7, 2016, (via email)
Dr. Charles Sachatello
I always enjoy hearing from you and especially reports about your liver-brain-theory. As you have emphasized, the ultimate test of the hypothesis would be liver replacement.
Thus, it would be very difficult, particularly in today’s climate to justify liver transplantation for the indication of ALS. Be that as it may, I continue to watch you initiatives with lively interest. With best regards,
Thomas E. Starzl, M.D., Ph.D.
Professor of Surgery
Starzl Transplant Institute
Accordingly I felt obligated to develop simple and inexpensive method to validate or refute the basic premise of the “liver brain theory.”
The first patient recognized to have clinical findings now diagnostic of ALS was described 194 years ago in London, England. (1824)
Today nearly two centuries later, there has been so little progress in the treatment of ALS that suicide is considered acceptable treatment in some Scandinavian countries as well as in more than a few well educated Americans. (10)
Proposed Methods to Reduce the Quantity of
"Hepatic Generated Neurotoxins"
The most certain procedure to confirm or refute the heritical premise (that hepatic generated neurotoxins are the proximate cause of ALS) would be to do a liver transplant (replacement). But as noted by Dr. Thomas Starzl in his prior comments, it would be extremely difficult, if not impossible, to do a liver transplant in our current environment.
The best second choice would be to study and evaluate a small group of patients with ALS by putting each of them on total parenteral nutrition for three to six months or longer. In view of the fact that the patient’s own liver would not be faced with the necessity of requisite metabolic breakdown of complex native proteins, it almost certainly follows that there would be a reduction in the production of hepatic generated neurotoxins. It logically follows that the fewer neurotoxins produced that the rate of muscle loss would be reduced and afflicted patients would live longer in most cases.
Unfortunately this study could be prohibitively expensive:
There are two primary costs:
(1) The paucity of patients with ALS in any give location would mandate the necessity of multiple study groups.
(2) The unproved unreliability of currently available measuring devices to record subtle changes in muscle strength would require a large number of patients, with appropriate controls to be enrolled in this study.
(3) The third and least expensive study group: Each patient will serve as his own control.
(All medications, foods (including alcohol), activities and travel as per usual during this first 12 week period.)
1. Use standard, locally available devices, measure and record muscle strength twice a week, Monday and Thursday for the entire 12 week period. Record biceps, triceps, grip strength as well as toe raising and quadriceps. (15) Make a determined effort to measure "biting strength".
2. During this entire period encourage the patient to consume his usual diet (including alcohol).
3. Hire a professional, certified dietician to calculate total caloric intake: Fats, Carbohydrates and Proteins separately.
4. Weigh one time per week, naked, on a very accurate scale.
5. Any and all travel and exercise programs as scheduled or desired including gym and swimming.
6. Engage the services of an interested mathematician.
1. Every detail exactly the same with the first 12 weeks but with one exception:
Proteins must be taken in the form of essential amino acids only.
A very recent controlled study (16) confirms that a special liquid diet extended the life of Alzheimer’s patients. I am in process of writing these authors encouraging them to repeat this study in ALS patients. It is extremely likely they will prove that this same diet will reduce the rate and extent of muscle loss in ALS patients and in doing so prove that they can extend the life of ALS afflicted patients.
A. Engage the services of a hospital pharmacist.
B. Engage the services of a Pediatrician who has experience in treating inborn errors of metabolism.
I propose these specific studies in view of the fact that one of the basic premises of the liverbraintheory: is that both ALS and Alzheimer's have a common cause; neurotoxins produced in the patient’s own liver.
By reducing the necessity of a patient's liver having to metabolize intact native proteins, we should be able to record a reduction in the quantity of neurotoxins produced, manifest by a measurable reduction in the rate of loss of muscle strength in ALS afflicted patients.
This study like all objective studies must have predetermined measurable criteria.
ALS specifically lends itself to this study due to our ability to measure objectively both the extent of loss of muscle strength in additional to the rate of muscle loss over time. Although there are no specific studies demonstrating whether the rate of muscle loss is either linear or exponential, the basic premise of the liverbraintheory is that hepatic generated neurotoxins result in the death of motor neurons in specific areas of the brain in patients afflicted with ALS.
An additional premise of this theory is that hepatic generated neurotoxins would be produced at a near constant rate while the number of specific central motor neurons would be reduced due to the continued production of hepatotoxins. In view of the increased ratio of neurotoxins to specific central motor neurons, the rate of loss of strength would tend to be slightlyexponential in the later stages of ALS.
By comparing the rate of muscle loss in the first 12 week period versus the second 12 week period, this study should confirm that these predicted findings are statistically significant: “the rate of muscle loss in the second 12 week period would tend to be linear but at an increased rate, compared to the first 12 week period.
Confirmation of the validity of this premise with other objective data should provide additional support for a liver transplant being offered to a patient dying of ALS.
As the author’s thoughts have evolved over a period of several years, he now believes that there is no longer a question whether there will be an ALS patient who volunteers for a liver transplant, but rather where it will be performed.
It is highly unlikely this procedure will be performed in the US. After considerable thought the author believes it most likely will be performed in a Scandinavian Country, when a parent there donates part of their liver to a son with ALS.
Published data from Sweden in particular, confirms that suicide is 6 times more common there in patients with ALS than in any other disease. (8) On a risk-reward basis, a successful liver transplant in a patient dying with ALS holds more promise for long term success than suicide does.
The best analogy supporting this observation is that the world’s first heart transplant was not performed in the USA, but rather in South Africa.
Although several major surgical groups in the US had demonstrated long term success in animals with heart transplants, they were reluctant to attempt to be the first group to attempt to do a heart transplant in the event of unanticipated surgical complication which could be career ending in today’s medical legal environment.
Today, nearly two thousand heart transplants are done yearly on a routine basis in the US with excellent long term results.
2/14/2016. Rev. 8/17/2016.
A more definitive technique to confirm the basic premise of this theory would utilize repetitive plasmapheresis. (Also to be referred to as “Plasma Exchange) 9
If the basic premise of this heretical theory is correct as the author thinks it is, Repetitive Plamapheresis in patients with ALS should be able to curtail the rate of progression of muscle loss and weakness simply by reducing the quantity of circulating hepatic generated neurotoxins which the author postulates to exist.
Equally important, the plasma removed from afflicted patients would provide a ready source for isolating and identifying the specific hepatic generated neurotoxin(s) promoting the development of ALS. It should be quite easy to isolate and identify the specific hepatotoxins which will be shown to be the proximate cause of ALS. (1)
Reproducible data confirming that the rate of loss of muscle strength in patients with ALS via repetitive plasmapheresis can be curtailed to an absolute minimum should provide sufficient evidence to warrant performing a liver transplant on several patients with ALS.
A single liver transplant which demonstrates it can permanently arrest the progression of muscle weakness, the hallmark finding in patients afflicted with ALS; will provide the ultimate confirmation and validation of the basic premise of the Liver-Brain-Theory.
Once the exact chemical composition and spatial configuration of these specific hepatic generated neurotoxins are determined, it should be relatively easy to develop specific medications (neurotoxic neutralizing agents) precluding the progression of additional muscle weakness in patients with ALS.
In my opinion, ALS will ultimately be treated as a chronic disease, just as diabetes is, whose progression can be curtailed by a combination of dietary changes and administration of specific medication (neurotoxic neutralizing agents).
Similar studies should lead to the discovery of specific blood tests to identify those individuals at risk to develop Alzheimer’s disease long before they have any manifestations of this terrible disease. Here too, it should be possible to develop similar medications precluding the possibility of developing Alzheimer’s.
In summary, I believe it is far more likely that we will in time be able to prevent the development of Alzheimer’s than we will ever be able to “Cure Alzheimer’s”.
Ref. (1): “No evidence suggests that Plasmapheresis has any role in RX …of ALS.” Consensus Conference 1986: Amer. Society of Neurology
The statement cited above appeared to be an afterthought at this consensus conference as there was no supportive evidence to warrant publishing it in 1986.
Rev. 10/14/2016, 4/12/2017, 5/14/2017 & 8/8/2018
September 27, 2016
Dr. Thomas E. Starzl,
Professor of Surgery
Starzl Transplantation Institute
Dear Dr. Starzl,
I have read and re-read your email of January 5, 2016 to me in which you state “it would be difficult, particularly in today’s climate, to justify liver transplantation for the indication of ALS.”
I fully respect your measured opinion and have strived to develop a series of non invasive studies which would support the heretical premise of my Liver-Brain-Theory, i.e. that the "proximate cause of ALS are neurotoxins produced in each patient's own liver."
I initially proposed two simple, inexpensive studies: (10 A & 10 B) that would provide supportive evidence for the Liver-Brain-Theory. I now am proposing a more specific study (10C) which has the potential to provide direct evidence that the proximate cause of ALS are circulating neurotoxins. This study has the potential to establish a dose relationship between the quantity of circulating neurotoxins and the rate of progression of muscle weakness.
The fundamental thesis of this newer proposal is that repetitive plasmapheresis will reduce the quantity of circulating neurotoxins and could be easily quantified by measuring the markedly decreased rate of change in the loss of muscle strength in patients with ALS which I anticipate you will observe.
Even more importantly, repetitive plasmapheresis will facilitate the acquisition of the plasma containing these specific ALS neurotoxins which I postulate to exist. It would only be appropriate that the first liver transplant to permanently arrest the progressive muscle weakness characteristic of ALS be done under the auspices of the Starzl Transplantation Institute.
I trust you might encourage several of your neurologists, or even a team of your transplant surgeons, to perform repetitive plasmapheresis on two or three patients with ALS. I am quite certain they will witness a near total cessation of progressive muscle weakness associated with repetitive plasmapheresis at least on a temporary basis.
These objective findings will provide supportive evidence to justify performing the first liver transplant in a patient otherwise certain to die from ALS.
With respect and admiration,
Next year (2017) will be the 50th anniversary of your first successful liver transplant. It would be quite timely to celebrate this accomplishment by demonstrating that a liver transplant (replacement) will permanently arrest the progressive muscle weakness characteristic of ALS and give afflicted patients a more normal life expectancy.
Dr. Thomas E. Starzl died March 4, 2017, a week shy of his 91st birthday.