A Simplified Explanation
Section 03

The Liver-Brain-Theory was conceived De novo,
By a non-neurologist physician, using nothing more than pure deductive reasoning.

“Degenerative Brain diseases share a common cause:
Neurotoxins produced in each patient’s own liver”.

  1. This is the most comprehensive theory ever presented addressing neurodegenerative brain diseases, and the only one whose basic premise can be both challenged and tested quite easily.

  2. One routine surgical procedure, a liver transplant, in a patient with ALS will either confirm or refute the basic premise of the Liver-Brain-Theory.

  3. Should a liver transplant prove that it can permanently arrest, but not reverse the progressive muscle loss characteristic of ALS the basic premise of this theory will have been validated. The specific hepatic generated neurotoxin(s) which the author postulates to exist will have been confirmed to be the direct proximate cause of ALS should be able to be isolated and identified shortly thereafter.

  4. This theory further proposes that Hepatic Generated Neurotoxins leading to other neurodegenerative brain diseases will be demonstrated to have a very similar structural and chemical configuration.

  5. It should be possible to develop specific protein blocking or neutralizing agents arresting the progression of either Alzheimer’s or “motor neuron disease” (ALS) within a year or two once the specific primary neurotoxic hepatotoxin causing either disease has been identified with certainty.

  6. The multiyear prodromal period observed in Alzheimer’s will be confirmed to be due to the time required for the liver to produce a sufficient quantity of neurotoxins necessary to destroy glial-neuronal cell complexes anatomically and physically adjacent to memory neurons leading to their death and the subsequent loss of each patients acquired memory.

  7. The much shorter prodromal period characteristic of ALS contrasted with Alzheimer’s will most likely be attributed to the much larger ratio of hepatic generated neurotoxins to motor neurons as opposed to the number of memory neurons. The fact that the time period of diagnosis to death in ALS is in the range of 10% -15% of the equivalent time period for Alzheimer’s will be shown to be a reasonably accurate measurement of the ratio of memory neurons to motor neurons.

  8. In time both these neurodegenerative diseases will be recognized to be a form of an inborn error of metabolism with a delayed recognition of onset. They will be demonstrated to differ from “storage diseases” in that the hepatic generated neurotoxins are not stored in glial neuron cell complexes but rather precipitate the death of specific glial cells and their anatomically associated memory or motor neuron complexes.

  9. An additional corollary of the Liver-Brain-Theory is that Alzheimer’s which develops in Down’s patients will be shown to have the same proximate cause as that seen in the general population: “hepatic generated neurotoxins.” The fact that clinical findings appear several decades or two earlier in Down’s patients is directly attributable to the observation that Down’s patients have fewer cerebral neurons at birth (13)

This theory provides a plausible explanation why the age distribution of ALS is slightly younger than Alzheimer’s is directly attributable the presence of more memory neurons than motor neurons.

The Liver Brain Theory does not attempt to explain why ALS is more common in white males in contrast to Alzheimer’s which is more common in females other than to cite published data that suggest females tend to have fewer cerebral neurons than males. (3)

Currently there are an estimated 5.4-5.7 million Americans with Alzheimer’s, several million with Primary Dementia’s and approximately 15,000 (+/-) with Lou Gehrig’s disease, (ALS) or “motor neuron diseases” as this disease is named in most European countries.

In 2016, a newly diagnosed patient with Lou Gehrig’s disease (ALS) will have a greater probability of death (95 %+) within 5 years than with most malignancies. The same for Alzheimer’s: here the probability of death within 8 -10 years of diagnosis approaches 85- 90% plus.

In a single declarative sentence the Liver-Brain-Theory proposes the following heretical concept:

“The primary inciting cause and subsequent clinical course of ALS, Alzheimer’s, Primary Dementias, Parkinson’s, senile macular degeneration in addition to many other degenerative nerve diseases result from the death of neuron-glial complexes directly attributable to the neurotoxins produced in the patient’s own liver.”(Hepatic Generated Neurotoxins)”

The basic premise of the Liver-Brain-Theory is that Alzheimer’s, ALS, Primary Dementias, Parkinson’s and senile macular degeneration in addition to other neurodegenerative diseases are more likely to be related to an aging liver, rather than to an aging brain!

If one accepts current thinking that neurons are primarily dependent on a glucose environment for their essential intra-cellular metabolism and usual function, the inescapable conclusion is that it is the death of anatomically adjacent glial cells per se, that precipitates the death of their anatomically adjacent, but essentially nutrient dependent memory or motor neurons resulting in neurodegenerative brain diseases. The death of adjacent neurons would appear to be the result of deprivation of essential nutrients ordinarily provided by anatomically adjacent glial cell complexes.

This theory further proposes that the basic mechanism of neuron cell damage and proximate cause of death of glial neuron complexes is essentially similar in all neurodegenerative brain diseases including ALS, Alzheimer’s, Primary Dementias, Parkinson’s, senile macular degeneration and other forms of neurodegenerative diseases namely to hepatic generated neurotoxins.

And to go one step further, the Liver-Brain-Theory makes another heretical, but reasoned argument:
“A liver transplant will likely prevent or arrest the inevitable progression of muscle weakness, the hallmark finding of ALS, Lou Gehrig’s disease and give afflicted patients a more normal life expectancy.”

Some basic definitions:

“Prodromal Period” The time during which a disease process is in existence but is not yet clinically evident or diagnosable. Many diseases, including brain diseases, begin so insidiously that even the patient himself is totally unaware of their existence. Certain cancers, for example, those in the abdomen, can grow to a very large size before the patient has any symptoms.

The prodromal phase of ALS is substantially shorter than in Alzheimer’s. The evidence in Lou Gehrig’s case is that ALS probably developed less than a year or two prior to the start of the 1939 baseball season, just a few years prior to his death in 1941.

“Dementia” Non vascular types,Primary Dementia(s)” Symptoms characterized by memory loss, impaired thinking and loss of social skills, severe enough to interfere with many of the more common normal daily life’s functions. Clinical observation suggests there is an enormous variation in both the severity and rate of progression of Primary Dementia from one person to another.

Alzheimer’s disease is the most common form of dementia. A substantial number, but presently undetermined percent of patients with Primary Dementia progress to develop Alzheimer’s. There is no definitive test or clinical observation that can date the exact time of transition from Primary Dementia to Alzheimer’s.

Parkinson’s Disease: A neurodegenerative brain disease estimated to afflict a million Americans is manifest by rigidity and uncontrollable tremors in many muscles in addition to psychotic behavior and memory loss in some afflicted patients.

Dementia, Vascular type: cognitive deficits directly attributable to insufficient blood flow to various parts of the brain. Specific clinical findings will prove to correlate directly with the exact areas and quantity of ischemic or infarcted brain.

A secondary, but equally important observation implicit to the Liver-Brain-Theory is that the majority of body organs do not function as well as they age, as they did when they were younger.

Only brain function improves with age: due to its necessity of acquiring a requisite data base to facilitate deductive and analytical reasoning promoting a singular human ability: conceptual thought and analysis. “But only for a finite period, until the brain itself, falls victim to the ravages of time, as is the inevitable fate of all living cells and organs”.

The best example supporting this concept and the one easiest to comprehend relates to the heart: “cardiac function.” The basic function of the heart is to pump blood throughout the body. It would be very difficult to find a random group of 70 year old individuals, whose hearts are as healthy and functional at age 70 as they were when they were forty to fifty years younger.

Kidney, (Renal) Function

The primary function of the kidney is to remove liquid waste from the body and to contribute to fluid and electrolyte homeostasis. Tests of kidney function and urine volume can be measured with exquisite accuracy. Kidney function decreases with age and the rate of decrease is accelerated by other associated diseases: diabetes and hypertension in particular and certain rare congenital diseases: EG: polycystic kidney disease

A specific example of how one body organ can do harm to another body organ is readily apparent. A secondary effect of a diseased kidney can lead to high blood pressure. Hypertension can weaken the heart by forcing it to work harder pumping blood against an abnormally high pressure gradient. (14) In an extreme example, uncontrollable hypertension can cause the heart to fail: “The heart will be the innocent victim of its own failing kidney.”

Although some might question the relevance of these ideas to the “Liver-Brain-Theory”, they were intentionally inserted to support the heretical premise that degenerative brain diseases are most likely result from the patient’s own aging liver.

The patient’s aging liver could very well be directly responsible for the development of Alzheimer’s, ALS, Parkinson’s, Primary Dementias and age related macular degeneration in addition to other degenerative brain diseases still without known cause.

The basic premise of this theory applies directly to the patient’s liver. The liver is the largest internal organ in the body with an average weight of 1,500-1,600 grams; approximately 3 1/4 lbs. One of the liver’s many important functions is to provide appropriately metabolized nutrients to other body organs, including both the brain and heart.

Neurodegenerative Diseases, Definition: “Neuro”, having to do with the brain, spinal cord or other nerves throughout the body

Degenerate: a fundamental biologic process during which individual cells or a group of cells gradually lose function and eventually die, leaving just scar tissue behind as evidence documenting where these specific cells previously existed.

Glial cells: physically adjacent supporting cells for neurons whether in the brain or elsewhere in the nervous system. There are several different specific types of glial cells, each with relatively distinct attributes and functions. One of the most important functions of glial cells appears to be to supply essential nutrients to their anatomically adjacent neurons.

XYZ has estimated that glial cells are 10 times more common in the brain than are neurons.

No brain cell (neuron) is capable of completely supplying its own specific nutrients required to thrive and function normally. Neurons are dependent on a complex, but poorly understood glial cell-neuronal relationship. Specific glial cells may well be the first cells damaged by hepatic generated neurotoxins, leading to the subsequent death of their nutritionally dependent neurons, perhaps by simple starvation.

These initial changes would be occurring long before they could be recognized or appreciated during routine clinical exams thus accounting for the fact that Alzheimer’s is truly a disease of aging. Non genetic Alzheimer’s disease is rarely diagnosed before age 60-65 using presently available diagnostic methods.

Alzheimer’s, ALS, & Primary Dementias

Alzheimer’s has been a recognized as a distinct and unique disease since 1906-7. Alzheimer’s disease robs senior citizens of their memory and their ability to think clearly and care for themselves. An otherwise healthy patient, diagnosed with Alzheimer’s will die within 5-10 years of his initial diagnosis. Death is precipitated by increasingly severe memory loss even to the point of failure to recognize hunger, the necessity of adequate caloric intake and importance of basic personal hygiene.

“Alzheimer’s is the only Cause of Death in America that Cannot be Prevented, Cured of Slowed”
(*Alzheimer’s Association)

ALS, Lou Gehrig’s disease, or motor neuron disease as this degenerative brain disease is named trough out the rest of the world is distinctly different in that it is charterized by the death of motor neurons: the nerves that instruct the body muscles to swallow, move and or breathe. ALS is recognized by the progressive development of irreversible muscle wasting, associated with loss of muscle mass and strength secondary to the degeneration of motor neurons in specific areas of the brain.

ALS is relatively rare. The incidence of new cases of ALS is estimated to be 4-6,000 per year, affecting 15,000 – 20,000 patients in America in contrast to more than 5.5 million patients afflicted with Alzheimer’s. Reasonably accurate estimates of the incidence and number of patients with a variety of Primary Dementias are much less certain.

ALS may develop in a few patients younger than thirty. The majority of ALS patients are white males diagnosed between ages 40-70. ALS was essentially unknown to both physicians as well the general public in America until it was diagnosed in Lou Gehrig in 1939. Gehrig was then one of the most prominent and best known baseball players in the world. He died at age 37, 25 months to the day he took himself out of the starting Yankee lineup, “for the good of the team”.

The typical clinical course of a patient with ALS is characterized by death, 24-60 months after it is initially diagnosed, usually due to loss of muscle strength required to breathe and swallow. A very small minority of afflicted patients live more than 10 years after initial diagnosis.

ALS has no known cause, cure or effective treatment. The FDA approved drug: Riluzol may add 3 months of additional life in some patients.

Initial Conceptualization of the Liver-Brain Theory

This heretical theory was conceived from the author’s personal health experience. In 2004 he was diagnosed with terminal liver disease of unknown. In the second half of 2005 the he was well aware he was losing his innate cognitive ability. In November 2005 he was unexpectedly advised to move to Pittsburgh in the event a liver became available on short notice. When the author attempted to pack he realized he was not sure what a suitcase was or what it was for. The coup de grace was that he needed help to close the zipper on his suitcase.

Almost by serendipity a “left over liver” became available on a moment’s notice on January 3, 2006. When he finally emerged from anesthesia many post operative days later he was in great pain but could not remember the word for “pain”. His subsequent clinical course characterized by a prolonged and profound loss of memory generated these heretical ideas.

As the liver ages, it almost certainly becomes less efficient in completely metabolizing normal substrates, including complex proteins or breakdown of waste products generated elsewhere in the body. Even more likely is that the liver might actually lose its ability to completely metabolize common substrates resulting in a few by products that are neurotoxic per se or have secondary neurotoxic effects.

Neurotoxic metabolites would have a propensity to harm all neurons in general but specifically those with receptors configured to interact with spatially compatible neurotoxins produced in the patient’s own liver. When viewed in an abstract manner, neurodegenerative brain diseases might be classifiable as an inborn error of metabolism with a delayed onset of recognition.

These simple concepts easily account for the following observations:

  1. The extended length of the prodromal period of Alzheimer’s: five to ten years plus.

  2. Clinical observation confirms that Alzheimer’s is progressive and that its incidence increases with age. This later observation is easily explainable by simple arithmetic; the quantity of hepatic generated neurotoxins produced would remain relatively constant while the number of cortical memory neurons would decrease due to their continued death resulting in an increased ratio of neurotoxins to memory neurons.

  3. The specific and relative unique clinical characteristics of ALS, Alzheimer’s and Primary dementias appear to result from the death of nearly identical glial-neuronal cell structures located in different, but specific areas of the brain.

  4. The delayed recognition and diagnosis of other types of primary diseases is most unusual. The overwhelming majority of late onset diseases are typically degenerative in nature: (E.G) osteoporosis, aneurysm formation, joint destruction, hearing or vision loss, and atherosclerosis.

Well established mechanisms of neuron cell death described in the excitotoxicity pathways might play a significant role in the development of some forms of neurodegenerative diseases. (3) Definitive evidence is lacking.

It has long been well recognized that the origin of Neurodegenerative brain diseases is independent of: Geography, Ethnicity, Sex, Religion, Diet, Skin Color, Ambient External Temperature, Occupation, Innate Intelligence Education and any and all other factors ascertainable. There is definitive evidence that the incidence of these diseases is influenced by race and nationality.

This proposed theory represents the cumulative thought processes resulting from reanalysis of all possible causes and origins of neurodegenerative brain diseases.

A theory or hypothesis is nothing but a possible roadmap, going nowhere in particular, but charting unmapped thought processes leading to the development of additional new ideas.

The development of “theories” is a critical step in the Scientific Method. This theory, like any other theory, must be subject to critical analysis, review, repudiation, rejection, or acceptance as warranted by specific conclusions of well-designed studies and experiments.

New ideas must be welcomed, not summarily rejected as is typical of the editorial policy of the majority of medical journals published today.

Fundamental to the Scientific Method is the inescapable conclusion:

Everything (including diseases) has a primary cause!

Updated and revised; 10/10/2016, 7/30/2018. CRS

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