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Cryptopyrroluria, nitrosative stress and mitochondrial disease
© By Dr. sc. med. Bodo Kuklinski
As a
result of previous medical tests to 821 patients (with ages varying from infancy
up to over 70 years) a positive correlation between pathologically increased cryptopyrrole
values and nitrosative stress was detected. Cryptopyrrolics indicate a high NO (Nitrogen
monoxide) synthesis, measured by detecting pathologically high citrulline amounts
in urine or by increased NO concentrations in the expired air.
Citrulline is an amino acid, which
is a by-product derived from the NO synthesis from
arginine + oxygen = NO + citrulline
NO and citrulline are not stable values.
They show very rapid fluctuations, especially under physical strain, which are
accompanied by a high oxygen consumption in the metabolic level, especially in
the mitochondria.
This NO synthesis is highly likely
the induced NO synthesis (iNOS).
With this diagnosis, many important
consequences concerning the thematic approach to diagnoses, therapies and
estimation of pyrroluria reveal, that it is not an autonomous form of disease, but
rather an accompanying symptom of an organic disease affecting several organs
NO is formed in four different
synthetic ways in the organism:
- Endothelial NO synthesis (eNOS). In this pathway, NO is formed in the
inner walls of blood arteries.
- Neuronal
NO synthesis (nNOS), the nerve cell is the place, where formation takes place.
Both NO forms are calcium –
dependent and serve as neural chemical messengers during the transmission of neuronal
signals.
- Induced
NO synthesis (iNOS) as a factor of the immune system. The induced form is
increased by bacterial, viral or parasite infections, but also by chemical
stimulation an.
- Mitochondrial
NO synthesis (mtNOS). Mitochondria form NO as a metabolic regulator for the
oxidative phosphorylation and thus for the cellular energy-(ATP)-synthesis.
NO has the property, to bind itself
on iron or especially on FeS-bearing enzymes and block them. This bondage is
reversible and can be broken up by partial pressure of the oxygen. This would
explain the hunger for oxygen of the affected patients.
The biochemical effects of an
increased NO synthesis are:
- Inhibition
of the FeS-bearing enzymes
in the mitochondrial respiratory chain, and particularly in the
complexes I and
II. As a result of this inhibition, less ATP is formed, but this
inhibition means
that at the same time an increased formation of superoxide from the
mitochondria
takes place, which is further augmented by physical strain, i.e.
increased metabolic activity.
- Inhibition
of the FeS-bearing aconitase
in the citric acid cycle. Through this inhibition the conversion of
citric acid
to isocitric acid is inhibited. The interruption of the citric acid
cycle means
a deficit in the availability of NADH, so that in this metabolic level
the
electron flow in the mitochondria is disturbed as well.
- A
further FeS-bearing enzyme is
the liver-7 a-hydroxylase,
which achieves the
conversion of cholesterol to bile acids. An inhibition of this activity
leads
therefore to an early increase in the cholesterol levels, an increase
which is
completely resistant to any diet and has nothing to do with nutrition
rich in cholesterol.
Other
iron-bearing enzymes, which react to NO are:
- the
cytochrome-c-peroxidase in the mitochondria
- the
lactoperoxidase
- the
myeloperoxidase
- thyroid peroxidase
- the uterine p
- Hemoglobin and myoglobin
- the catalase
- the ferochelatase
- and other enzymes
Due to the fact that in mitochondria
functions such as the cell respiration, the ATP-synthesis, the citric acid cycle, the fatty acid oxidation, the
glutamine synthesis, partially the steroid
hormone synthesis and the beginning of the glucose- new formation (gluconeogenesis)
take place, massive metabolic deficits are developed, which in turn are expressed clinically
in form of disturbances in blood synthesis (e.g. porphyria), in lactose intolerances,
above all however in a chronic energy deficit. This effect is noticeable
particularly in the organs with high energy demands such as the central nervous
system and the musculature. Affected patients suffer from a chronic energy
deficit; they are easier fatigued, need longer relaxation breaks, the ability
to concentrate is possible only for short periods of time. Stamina performances
in particular, that need energy derived from the fatty acid oxidation, are
almost impossible. The continuous feeling of hunger forces the affected persons
to always eat; carbohydrates however, often block the energy production further
(pyruvate dehydrogenase deficit in the mitochondria), so that this resulting
continuous urge to eat does not replace the energy deficit, but, on the
contrary, augments it. Energy carriers of the carbohydrates can not be utilised,
instead they lead to a compulsory fat synthesis, whereas proteins and fatty acids
can be better utilised energetically, since they can enter the citric acid cycle
through the acetyl coenzyme A.
A clinical result of this effect is the
tendency to increased fat deposition, chronic hunger, chronic hypoglycaemia and
tendency to high cholesterol levels. The inhibition of the citric acid
formation increases further the energy deficit, since the acetyl coenzyme A can
not be expelled from the mitochondria in the cell, because this expulsion is only
possible via the citrate-shuttle.
Further consequences are disturbances
in the blood formation (hemosynthesis), so that porphyre diseases may arise,
chronic immune insufficiency with affinity for infection, thyroid gland malfunctions
or a reduced availability of g-amino butyric acid (GABA).
The chronic energy deficit is
consequently expressed in a chronic tiredness and fatigue syndrome.
The amino acid citrulline has the property
to be stored in certain proteins such as e.g. fibrinogen. This citrullinated fibrinogen
acts as an antigen and triggers auto immune reactions, i. e. aseptic (not bacterial)
inflammatory reactions especially in the joints and the spinal column, so that
as a result chronic crucial joint complaints or even chronic pains in the lumbar
spinal column arise, which have nothing to do with physical strain. If there is
a longer chronic condition, joint rheumatism may be developed.
The blocking of mitochondrial energy
metabolism has the effect, that mitochondria become literally free radical
cannons, which trigger an oxidative stress. If additional chemical stimulations
occur, then the Th1-lymphocytes release increasingly Interferon g, which in turn is a strong stimulant
for a further iNO synthesis. Aseptic inflammatory reactions trigger the release
of tumour necrosis factor a, which in the course of the inflammatory
process leads to an increased iNO-formation as well.
This chronic energy deficit forces
the cells, in order to maintain their survival, to turn on secondary “emergency
power supply aggregates“such as the membrane bound NADH-Oxidoreductase or the
aerobic glycolysis. At the same time proto- oncogenes are activated. In addition another effect takes
place, namely that NO in the body leads to an increase in the formation of nitrosamine,
so that here a higher risk for genetic mutations is developed.
During this chronic energy deficit
brain cells are in a particular dilemma, since the sedating GABA-influence no
longer exists; instead glutamate receptors take over. The calcium influx
induced by this effect due to the lack of energy in the brain cells can not be replaced;
a continuous calcium overload takes place in the cells and leads to hyperactivity,
high irritability of the brain. The activation of the glutamate-NMDA-receptors
generates superoxide (O2°-).
This increased formation of superoxide
through the glutamate receptor, die mitochondrial release of superoxide and the
superoxide formation rates due to chronic inflammatory processes as well as the
membrane bound NADH-oxidoreductase lead to a further worsening of the situation,
since NO together with the superoxide free radicals form the toxic peroxynitrite
(ONOO°).
NO has the property, to bind itself with
a higher affinity to superoxide than superoxide to the detoxifying superoxide dismutase
in mitochondria (manganese -dependent) and in the cell plasma (copper
superoxide dismutase and zinc superoxide dismutase). With the formation of
peroxynitrite the mitochondrial function is irreversibly impaired.
NO°
and O2°
create a lethal cocktail!
Peroxynitrite is highly toxic, has
an oxidative function and is stored on aromatic amino acids such as tryptophane
or its by-products such as serotonine. The storage in phenylalanine leads to storages
in tyrosine or catecholamine for example, so that even auto immune reactions in
the thyroid gland and in the neurotransmitters can be triggered. A typical example
is the Hashimoto thyreoiditis. The storage products are nitrated amino acids,
e.g. nitrotyrosine, which nowadays are detectable, just like citrullinated peptides.
Peroxynitrite and nitrated amino acids
can be traced at early stages during chronic inflammatory processes, especially
in the nervous system as well as in multiple sclerosis, amyotrophic lateral sclerosis,
but also in arteriosclerosis and other diseases. As a result, disturbances in
the hormonal household and in the neurotransmitters in the brain occur. By a chronically
increased ONOO° formation the risk of auto immune
diseases is increased as well.
With the irreversible inhibition of
the mitochondrial function and the permanent firing by oxygen free radicals cells
and cell nucleus DNA are damaged, and in addition damage in the mitochondrial
genome takes place. Mitochondria possess a round-shaped genome, consisting of 37
DANN molecules, which due to low histone protein content are not reparable. The
damage of the mitochondrial genome does not occur immediately, but rather after
a certain incubation period. The reason is, that each mitochondrial gene possesses
500 to 1.000 copies. If 5 to 10 % of the copies are damaged, clinically there
is still not an important loss in the performance. The degree of heteroplasmy
amounts only 5 to 10 %. If
this degree is increased to 40 or 50 %, obvious losses in the performance of mitochondrial
functions are indicated. Most often disturbances in the pyruvate kinase accompanied
by disturbances in the carbohydrate breakdown are encountered. Carbohydrates from
sugars and nutrients can not be broken down to energy. They lead to a lactacidosis
with a lactate to pyruvate ratio higher than 10: 1. Through the formation of
the lactacidosis the metabolic disturbances and fatigue are worsened.
Mitochondrial genetic damages are
inherited from the mother, not from the father. This explains among others, that
cryptopyrroluria can also be inherited.
Since NO disturbs the blood
formation as well as the function of other blood bearing substances, a cryptopyrroluria
occurs. During the daily course it shows strong fluctuations, can be evaluated as
a stress factor for the nervous system and leads to the known deficits in vitamin
B6 and zinc. These deficits are not detectable by serological analyses. Much
more convincing is the analysis for cystathionine in the urine. It is
increased, when the vitamin B6 demand in the organism can not be met, although
serum values may still lie in the standard range or even higher. A zinc deficit
can be indicated especially by intracellular analyses, less by serological
analyses.
Within the context of the mitochondrial
diseases, cryptopyrroluria is for the survival function of the body an
important regulatory quantity. The zinc deficit is important, since numerous kinases
become inactive because of it and the phosphorylation of vitamin B6 and vitamin
B1 is no longer possible to full extent. Therefore secondary deficits occur due
to a vitamin B6 deficit, e. g. neurotransmitter formation, protein synthesis and
transamination reactions. The low zinc levels are probably desirable by the
organism, because during low energy yield situations the intake of zinc would additionally
inhibit the aconitase in the citric acid cycle and apart from that, zinc
activates further the glutamate receptor (NMDA receptor). In such a situation
the energy deficits and the state of irritability would increase. The brain has
priority for the maintenance of its performance ability and for the securing of
minimal energy availability. Disadvantages are vitamin B6 utilisation
disturbances, but also the increased risk for further disorders/diseases. Particularly
rich in zinc is the retina, the prostate gland and the hippocampus, an organ responsible
for the conversion of the short term memory to long term memory in the brain. By
a zinc deficit, vitamin A can not be transported either, since the protein binding
retinol is dependent on zinc.
This situation explains the fact
that cryptopyrrolics often react with massive side effects to a zinc intake. Light
forms instead, show rapid clinical, cerebral improvements by administration of
vitamin B6 and zinc. In light cases the affected persons indicate a strong appetite
for meat dishes, in severe cases there is an aversion against meat, since the conversion
of muscle protein to body own protein is dependent on vitamin B6 and if there
is a corresponding strong deficit in zinc and/or Vitamin B6, the organism can
not break down normally foreign proteins.
A chronic energy deficit in the nervous
system often leads to an additional activation of C nerve fibres. These surround
mast cells in a network form, so that by irritations increasingly histamine is
released. The chronic histaminosis (histadelia) has a stimulatory action to the
brain and peripherally it is a question of time, when allergies against
external factors (pollen, dust etc.) would occur. The affected persons are not
diseased because of the pollen, the mites etc. to allergic reactions, but
rather to an increased release of histamine and a disturbed break down of histamine.
The diamine oxidase needs copper and
vitamin B6 for the breakdown of histamine. Although in the brain there is no
DAO available, many methylation reactions, which need S-adenosyl methionine, take
place. S-AM however, in order to maintain its reactivity, needs an adequate methionine
supply obtained by meat as well as a adequate supply of vitamin B6, folic acid and
vitamin B12. If not enough meat is consumed, affected persons have an
additional deficit in vitamin B6, Vitamin B12 and methionine. Because of
this the brain and the peripheral organs can not break down histamine adequately. Besides, S-AM is necessary for the synthesis of
adrenaline, the formation of the sleep hormone melatonine from serotonine and for
the synthesis of polyamines such as spermidine and spermine, which play an
important role during cell division and cell maturity.
A zinc deficit leads to functional weakness
of the Zn/Cu superoxide dismutase. Apart from that, by zinc deficit glutathion-S-transferases
become inert. Affected persons show a very sensitive reaction to foreign and
harmful substances. In addition, NO inhibits the cytochrome P450 enzymes, which
are very important for the phase-I-detoxification.
The metabolic consequences of a mitochondrial
disease are significantly more serious, about which there will be no further
detailed description at this point.
As a summary we observe and identify,
that cryptopyrroluria signals only a concomitant symptom of a significantly
more serious disturbance in the mitochondrial level, which triggers performance
deficits in several organs and if not attended properly, leads to massive health
disorders in a multi organic level.
Mothers with KPU and mitochondrial
diseases portray an increased risk for complications during pregnancy. NO activates
the uterine contractions and opens the cervix. Consequences of this effect are
premature births.
Metabolic deficits and the chronic
NO surplus lead to disturbances in the maturity of the infant brain. Visual, acoustic
and motoric centres, the interconnection of the right and left brain
hemispheres, the dominance of the left temporal lobe are under developed, exactly
as the interconnection of neurons with each other. These children grow up with obvious
neurological and psychological deficits. Children with ADHS have a brain volume
smaller by 3 % than without ADHS.
Further symptoms of mitochondrial
diseases are an higher risk for neurodermatitis, nasal polyps, inflammations of
the middle ear, bronchitis, allergies and many more diseases. The
physician speaks of comorbidities, but they are not.
The result of the above is that the
treatment for pyrroluria only for light forms is the administering of B-vitamins,
zinc and other micronutrients, because in the end cryptopyrroluria must be
treated as a mitochondrial disease. This treatment is only possible by using micronutrients,
which have an influence upon the electron transport of mitochondria and secure
an improvement of the citric acid cycle.
If we observe the diseases appearing
in childhood such as ADS, ADHS, syndromes of neurodermatitis, fatigue, pain and
allergy of children, we notice that these are not isolated diseases, but rather
always the expression of mitochondrial disease, since they can be detected by
the increased NO rates of formation or of citrulline synthesis.
A cause-oriented therapy is consequently
possible only with mitochondrial treatment measures, however not with the
symptomatic treatment with Ritalin, corticoids or other medication, which act
upon the immune system. The development of allergies against proteins in early childhood
are not by themselves allergic reactions, but rather the expression of an
increased release of histamine, a disturbed breakdown function of histamine and
a nitrosative stress. Numerous dipeptidases
of the small intestine (enzymes breaking down proteins) can only act in the
presence of zinc (zinc- dependent). Some allergies such as protein allergies or
cow-milk allergies are caused by this effect. Since by these mitochondrial
diseases, disturbances in the breakdown of lactose, fructose and gluten are
unavoidable, such symptoms are developped. It would be wrong to place children
and youths on a diet, since this is not a therapy treating the primary cause. High
NO and histamine open and consequently damage the blood brain barrier. This
way, disturbances in the nerve cells in the long run are unavoidable. By
numerous affected persons a pathological increase in the brain barrier protein S-100
or the neuron specific enolase could be detected.
With the mitochondrial therapy, numerous
symptoms/ diseases such as neurodermatitis, the fatigue syndrome, exhaustion,
pains in the cervical spine, in the joints and allergy can be treated
successfully at the same time.
Apparently old known facts, if seen
from the point of view of the mitochondrial disease and of the nitrosative stress,
can result to completely new, scientifically founded and causal therapy
possibilities, which so called evidence based therapy measures such as
treatment with ritaline of children with ADHS, treatment of neurodermatitis with
immune modulators or calcineurine inhibitors, corticoid therapy of allergies etc.
remove the indication.
Finally, cryptopyrroluria is a symptom
of a mitochondrial disease.
Doz. Dr. sc. med. Bodo Kuklinski
Specialist
for internal medicine /Environmental medicine
Rostock, 26.
November 2004
Doz. Dr. sc. med. Bodo
Kuklinski
Specialised Medical
doctor for Internal Medicine/Environmental Medicine
President of the
scientific advisory council of the Nutrition Academy of Salzburg
Diagnostic centre and
therapy centre for environmentally caused medical illnesses
Wielandstr. 7, 18055 Rostock, DEUTSCHLAND
Tel. ++49 (0)381 – 470 74 70,
Fax: ++49 (0)381 – 490 74 72
E-Mail: kuklinski@ngi.de
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