6 Biochemical Markers in NAD Therapy
"This is mitochondrial medicine ... We can fix these blockage but they have to be understood by competent laboratory work and interpretation... There is nothing accidental or random... You go to the biochemical substrates and look at them instead of covering it up with drugs... A rational person will not oppose simple blood and urine studies for additional study of their case, especially when faced with the possibility of being on drugs the rest of their lives. A rational person will not feel threatened by this. When I approach physicians and talk to them, to partner with them to get the tests I want ordered for a patient, I rarely encounter resistance"674
"This is mitochondrial medicine ... We can fix these blockage but they have to be understood by competent laboratory work and interpretation... There is nothing accidental or random... You go to the biochemical substrates and look at them instead of covering it up with drugs... A rational person will not oppose simple blood and urine studies for additional study of their case, especially when faced with the possibility of being on drugs the rest of their lives. A rational person will not feel threatened by this. When I approach physicians and talk to them, to partner with them to get the tests I want ordered for a patient, I rarely encounter resistance"674.
Existing blood tests, which are internationally available, are used and provide good indicators of a person's biochemical energy level. The two tests, which are used, are the lactate and pyruvate tests. The person's lactate and pyruvate are measured in venous blood by pathologists and the results are used to determine three energy values. The tests can also be conducted on arterial blood, cerebrospinal fluid and tissue biopsies from affected organs, to obtain more accurate results. The blood tests are generally available from most pathologists. Prior arrangement must however be made, to ensure that the required test tubes are available. The large range of normal values of the tests provides for 95% of the variation in the normal population. The chance that someone will present with EMD, is therefore only 5%. Blood tests, which were conducted by independent pathologists for Alkogen on more than 2 000 persons with one or the other form of EMD or EMDRS, indicate that 87% exhibit a deviation in respect of one or more of the energy values. This finding is also reported in the more than 600 scientific articles, which were consulted.
"Concentrations of the energy-related substances lactate, pyruvate, glucose, and hypoxanthine were measured, and the lactate/pyruvate ratio was calculated".280 "Lactate and Pyruvate: These two compounds provide useful insight to basic metabolic factors due to their position in the physical energy production process. Pyruvate is the anaerobic breakdown product of glucose. Its further conversion to acetyl-CoA requires the pyruvate dehydrogenase enzyme complex. Pyruvate dehydrogenase requires cofactors derived from thiamin, riboflavin, niacin, lipoic acid, and pantothenic acid for optimal function."532 "Laboratory studied showed elevated levels of lactate and pyruvate in cerebrospinal fluid (CSF), without notable elevated levels in serum.643"
6.1 ENERGY VALUES DERIVED FROM THE BLOOD TESTS
The separate measurement of lactate and pyruvate, as well as the ratio between the two, provide a unique perspective of the energy metabolism, as well as several cues on how to improve the production of physical energy. In order to make it more comprehensible, it was transformed into three Energy Values each with a normal value at 100+. An energy value of 100 (borderline value) only means, that there is enough physical energy available for an ordinary day. Energy values higher than 100 means that the person has enough physical energy to engage in new projects or can handle daily demands more effectively. Most people shy away from new concepts and therefore it was decided, to refer to it as "energy values", because these are indicators of the metabolic energy production. The debt of chemical energy is visible in cellular, tissue and organ damage and loss of quality of life over time.
Due to the general low physical energy levels of EMD patients their blood are collected in a non fasting state, but the normal range for fasting values are used in the calculations of the Energy Values. Venous blood samples of more than 9 200 patients with EMDRS related complaints were collected at Alkogen of which 87% clearly showed an energy metabolic deficiency. Follow-up blood tests after 6 week of supplementation showed an improvement in the average energy blocks of patients from 52 to 81. International research show that clinical improvement takes up to 12 weeks. Follow-up blood tests are now only done after 12 weeks of treatment. Physical energy is visible in cellular, tissue and organ damage and loss of quality of life over time.
6.2 ENERGY VALUE I (Lactate to Pyruvate Ratio: Normal Range <=10)239, 749
This value is an indication of the ratio between the measurements of lactate and pyruvate, and provides a reliable measurement of the NAD levels in the blood. The normal value is set at 100+ and values, which are lower than 100, indicate the possibility of an NAD deficiency. On their own, the two blood measurements might seem to be very good, but if they are viewed in relation to each other a more reliable indication of the real availability of physical energy becomes clear.
Formula for Energy Value I (Normal Value is 100+)
Use both of the Pyruvate and Lactate values reflected on the blood test results
This formula is based on the following biochemical reaction that continually takes places in our bodies:
10 x Lactate = 1 x Pyruvate
Energy Value I can be explained better, by comparing it to the concepts of financial assets and liabilities, and the relationship between the two, which is referred to as liquidity. Someone could be a millionaire if you look at his assets alone, but if his liabilities is taken into the equation and it greatly exceed his assets he is actually technical insolvent. Amongst the almost 9 200 patients, who were tested at Alkogen, 53% deviated in respect of this value. Deficiencies on this value improve with NAD supplements.
∙ "Measured enzymatically in blood or CSF as an index of impaired pyruvate metabolism due to defects of glucose oxidation (fed state) or gluconeogenesis (fasted). The ratio of lactate to pyruvate reflects the NAD/NADH ratio and is useful in distinguishing primary defects of pyruvate metabolism from defects of electron transport (or oxidation).49
∙ Lactate itself is a dead-end metabolite, metabolized only by lactate dehydrogenase. The extent and direction of that reaction is determined by the free [NAD]/[NADH][H+] ratio of cytoplasm with which lactate and pyruvate are in near-equilibrium. Pyruvate is a crossroads of most of the major degradative and synthetic pathways, but present in about one-tenth the amount of lactate. Information on the content of both lactate and its redox partner pyruvate is likely to provide more information on the metabolic state of tissue than are measurements of lactate alone."239
∙ "The accumulation of intermediates reflects the increased lactate-to-pyruvate ratio; this leads to a secondary imbalance of the nicotinamide adenine dinucleotide-to-reduced nicotinamide adenine dinucleotide (NAD-to-NADH) ratio".235
6.2.1 Increased Lactate to Pyruvate Ratio
The lactate to pyruvate ratio proved to be the clinically most useful parameter in the evaluation and monitoring of mitochondrial diseases, showing higher sensitivity than lactate measurements only293. One study shows that lactate and pyruvate concentrations increase slightly at low levels of exercise without a change in lactate to pyruvate ratio until a threshold work rate at which lactate abruptly increases without pyruvate. The resulting increase in lactate to pyruvate ratio is progressive as work rate is stepped up and suddenly reverses when exercise stops297. A normal profile, even after stress and loading, does not rule out an inborn error of lactate to pyruvate oxidation436.
6.2.2 NAD Deficiency
The coenzyme nicotinamide adenine dinucleotide (NAD) plays a fundamental part in many enzyme reactions involved in all cellular energy production282. NAD and its derivatives' NADH, NADP and NADPH have regulatory functions in the generation of triose phosphates and pyruvate from glucose366. "Measured enzymatically in blood or CSF as an index of impaired pyruvate metabolism due to defects of glucose oxidation (fed state) or gluconeogenesis (fasted). The ratio of lactate to pyruvate reflects the NAD/NADH ratio and is useful in distinguishing primary defects of pyruvate metabolism from defects of electron transport (or oxidation)49. A higher level of lactate to pyruvate is characteristic of NAD deficiency265. Low levels of physical energy in cells can play a role in the development of various diseases. Various factors can provide an explanation for low levels of energy in cells of which NAD deficiency is one of the major role players51.
6.3 ENERGY VALUE II
(Increased or Decreased Pyruvate Level: Normal Range 0.03 to 0.08)
As has already been explained, pyruvate must be converted by various co-factors into particles, which can be used by the energy factories. If too much pyruvate accumulates, which usually happens as a result of too few co-factors, or if too little is available, production of physical energy cannot occur to an adequate extent.
Formula for Energy Value II (Normal Value is 100+)
Use only the Pyruvate value reflected on the blood test results
The metabolic basis for this formula can be oversimplified viewed as follows:
Pyruvate + NAD + CoA -> ATP + H2O + CO2
Pyruvate + NADH -> Lactate +NAD
Deviations in respect of this value is like having money in the bank, but not being able to withdraw it for use. Amongst the approximate 9 2000 patients, who have already been tested at Alkogen, 54% showed deviations and 12% had borderline values. Research indicates, that various pathological conditions are in particular associated with increased levels of pyruvate. Low Energy Values II improves with NAD and co-factor supplementation.
6.3.1 Increased Pyruvate Level
Increased blood pyruvate levels are reported in several disorders, including liver disease, congestive heart failure, diabetes mellitus, muscular dystrophy, thiamine deficiency, and various tumorous disorders281. Elevated levels of pyruvate may reflect a failure of the enzyme due to a functional need for cofactors derived from thiamin, riboflavin, niacin, lipoic acid, and pantothenic acid for optimal function. Levels of pyruvate in the tissues are further controlled by the biotin-containing protein, pyruvate carboxylase, which controls the first step in the reformation of glucose from pyruvate. Multiple forms of pyruvate carboxylase deficiency, some of which are biotin responsive, have been reported278, 532.
6.3.2 Decreased Pyruvate Level
Low pyruvate levels indicate an accumulation of NADH and probably reflect severe mitochondrial dysfunction279.
6.4 ENERGY VALUE III
(Increased or Decreased Lactate Level: Normal Range 0.50 to 2.20)
This value indicates, that there is too much or too little lactate in the blood. The normal value is again set at 100+.
Formula for Energy Value III (Normal Value is 100+)
Use only the Lactate value reflected on the blood test results
This formula is based on the following biochemical reaction that continually takes places in our bodies:
Lactate + NAD -> Pyruvate + NADH
Lactate accumulates as a result of many factors, amongst others exhaustion as a result of activity or other causes. Too little lactate creates problems in respect of physical energy for the organs, which use it as a source of energy. Lactate + NAD is converted into Pyruvate + NADH. Research indicates, that various pathological conditions are associated in particular with increased levels of lactate. Amongst the approximately 9 200 patients, who were tested at Alkogen, only 16% suffered from deviations in respect of this value. Low Energy Values III improves with NAD and cofactor supplementation.
6.4.1 Increased Lactate Level
“Lactic acidosis in infants is a serious emergency. The vast majority of cases have an acquired cause. These include IV glucose given to a newborn; shock, even hypoxia, from different causes; infectious and parainfectious causes (eg, sepsis even without shock, bacterial meningitis, urinary tract infection with the lactate-producing bacterium Enterobacter cloacae, Reye syndrome); poisoning by salicylates; seizures (seizures lead to increase in CNS lactic acid that results in increase in systemic lactic acid as in patients with bacterial meningitis); liver failure; and short gut syndrome.”750 Symptoms associated with inherited form of lactic acidosis is: episodic lactic acidosis from early infancy, failure to thrive, and hypotonia with or without features that may suggest specific defects.
Lactic acidosis is associated with both inherited and acquired metabolic diseases. Lactic acid metabolism in the presence of altered gluconeogenesis, anaerobic glycolysis, and acid-base balance is a major factor in many disorders. Lactic acid can be formed only from pyruvic acid; therefore, disorders that increase pyruvate concentration, enhance lactic acid formation, or reduce lactic acid degradation cause lactic acidosis. Inborn metabolic errors that are accompanied by derangement of metabolic pathways of glucose, pyruvate, amino acids, and organic acids as well as toxic and systemic conditions that promote tissue hypoxia or mitochondrial injury result in lactic acidosis.536
“Patients exhibiting a disorder of lactate metabolism suffer a high hospital mortality rate and are at risk for developing multiple organ failure. The mortality rate of critically ill patients with a blood lactate level greater than 5 mmol/L and an arterial pH less than 7.35 is 75% at 6 months.”751
To date, no therapy specifically designed to lower arterial blood lactate levels has reduced mortality significantly541. Lactate accumulates when there is a block in the final oxidative phosphorylation stage of energy production. Such a block results in the inactivation of the Krebs cycle. Increased lactate is a common condition that can be caused by a variety of metabolic problems532. The ability of the mitochondria to oxidize substrates and generate energy is integral to normal homeostasis and to the ability of cells to survive in the face of impending energy failure. Lactic acidosis is a common and readily visible biochemical marker for mitochondrial dysfunction. Lactic acidosis represents only the most obvious example in which acquired or congenital abnormalities of mitochondrial energy generation contribute to the expression of a broad spectrum of clinical disorders360.
Research findings suggest that elevated CSF lactate levels reflect the severity of metabolic impairment of the brain301. Disorders of the mitochondrial energy production can manifest in many tissues and may lead to various types of diseases. Since defects can occur on many sites of the oxidative phosphorylation system, molecular diagnosis can be difficult. Lactate measured in various body fluids is still the best selective screening parameter503.
Acute lactic acidosis may actually present with no clinical symptoms or be manifest by a variety of nonspecific symptoms such as fatigue, confusion, stupor, and coma. Respiratory collapse and shock may occur632. Numerous specific disorders affect oxidative metabolism. Lactate elevation frequently occurs and additional laboratory abnormalities often assist in focussing investigation. Diagnostic specificity may require, besides the blood and urine studies, tissue sampling, cerebral imaging, in vivo studies of tissue energetics, or molecular genetic analysis363.
“However, either lactate overproduction or impaired elimination alone is insufficient to explain the development of lactic acidosis, because the liver has a large capacity to eliminate lactate via gluconeogenesis and oxidation, some patients with lactic acidosis have minimal or no liver metastasis, many with widespread liver metastasis or serious liver disease rarely develop lactic acidosis, the kidney is able to excrete about one third of lactic acid and, moreover, in one study, lactate overproduction by tumor cells was not demonstrated.”707
“Infant patients with "cerebral lactic acidosis" show neurological symptoms, elevated levels of lactate in CSF, little or no systemic acidosis and levels of lactate in blood so slightly elevated that they would be overlooked. Lactate elevation confined to CSF and brain has been described in biotinidase deficiency and in some mito-chondriopathies.”727
6.4.2 Lactate Induced Sensitivity
Lactate infusion is currently the most universally studied of the pharmacological challenge tests in panic disorder. Analysis of lactate infusion studies to date suggests that patients susceptible to panic attacks are much more sensitive to lactate than are healthy controls or patients with other psychiatric disorders without panic attacks311. Sodium lactate infusions induce panic attacks in patients with panic disorder, but not in control groups. Late panickers had significantly elevated baseline cortisol levels445. Significant predictors of lactate-induced panic were prelactate infusion fear and the interaction of high cortisol levels and low hyperventilation levels444. Prolactin levels increased in all groups during lactate infusion. The elevated baseline prolactin for male panickers supports a relationship between prolactin and anticipatory anxiety446. Lactate-induced panic was associated with significant blood flow increases bilaterally in the temporal poles; bilaterally in insular cortex, claustrum, or lateral putamen; bilaterally in or near the superior colliculus; and in or near the left anterior cerebellar vermis450.
6.4.3 Decreased Lactate Level
Decreased lactate is seen in people with very little physical activity. Highly trained athletes have such efficient conversion of lactate to pyruvate that they also display lower lactate levels278.
6.5 THE ENERGY BLOCK: (Lowest Value of Energy Values I, II or III)
When looking at the energy blocks of the almost 9 200 patients, who have already been tested at Alkogen, one sees that as many as 87% had problems with one or more of the energy values. A further 5% had borderline values of 100.
Energy Block (Normal Value is 100+)
Lowest Value of Energy Value I, Energy Value II or Energy Value III
Elevations in lactate and pyruvate are markers for a variety of metabolic blocks278. Production of physical energy in cells consists of several biochemical processes. The cellular production of energy is possibly only as effective as indicated by the energy block, because the processes take place in interdependent cycles. The energy block indicates the lowest of the three energy values and what might be the reason for the chronic fatigue or the problem for which help is sought. It is, for example, like a watch which consists of several gears. If one of the gears malfunctions, it however affects the functioning of the entire watch negatively.
∙ These tests reflect the physical energy values in the venous blood.
∙ It is more accurate in arterial blood, cerebrospinal fluid and the effected tissue. In case of substance abuse or use of pain killers the physical energy values are falsely increased and more accurate values will be available after 6 weeks of use of supplementation.
∙ NAD supplementation only shows clinical improvement after 4-12 weeks of treatment.