CommentaryABSTRACT
Keywords: Atomic Emission Spectrometry of Hair; Metal-Ligand Homeostasis; Self- Organized Criticality; Epidermis
Commentary
The appearance of this commentary on the recently published
article “Distinctive features of criticality in the work of membrane
Na+/K+-ATPases” in the journal Acta Scientific Clinical Case Reports,
(2021), 2(8): 84-90 [1] is explained by the authors’ desire to
discuss the correctness of using hair spectrometry for assessment
of elemental homeostasis in the human body in toto. It is for this
purpose that the mentioned methodological approach continues to
be applied in many medical centers.
Our own research in this area, which is mainly associated with the
study of metal-ligand homeostasis (MLH) using hair spectrometry,
casts doubt on the applicability of this method for assessing MLH of
the whole organism. The trouble is that the widespread assumption
that the level of one or another metal in the hair is indicative of its
content in the whole body has not confirmed, despite numerous
attempts in the clinic and in the experiment. Such extrapolation
is not only unjustified but also potentially dangerous, since it can
become a source of diagnostic and “treatment-correction” errors.
Our own experience of many years of research and clinical
observations gives us grounds to assert that the quantitative shifts
of metals in human hair depend mainly on the transmembrane
transport of metals at the local (cellular) level and are in no way
associated with possible disorders of MLH of the whole organism.
The validity of this statement follows from the already known
features of sodium (Na) and potassium (K) homeostasis in the
human body, which is usually judged by the content of these metals
in plasma, urine (and, if necessary, in other biological fluids), as
well as by changes in ECG (in case of potassium imbalance) and
characteristic clinical picture.
It is difficult to overestimate the participation of cations Na+
and K+ in general homeostasis. Suffice it to recall the ability of
sodium cations, which are (unlike K+) mainly in the extracellular
environment, to retain water and (due to osmolality) to take part
in maintaining the water-electrolyte balance. The predominantly
intracellular localization of potassium cations determines their important role in the generation of membrane potential and in
other reactions of cellular metabolism.
It is no coincidence that there is a powerful, well-coordinated
regulatory system that works on the principle of feedback to
ensure the optimal content of Na and K in the body. It includes
endocrine (hypothalamus, pituitary, adrenal cortex) and other
organs (kidneys, lungs, intestines, skin), well-known hormones:
vasopressin, aldosterone, myocardial natriuretic hormone, etc., as
well as vascular baroreceptors and hypothalamic osmoreceptors.
Not all details of this homeostatic control are fully understood,
but its rather high level is undoubted, as one can judge by the
relatively small fluctuations in the normal content of Na and K in
plasma (Na: 135 - 152 mmol/l; K: 3.6 - 6, 3 mmol/l) and in urine
(Na: up to 340 mmol/day; K: 39 - 91 mmol/day). And although
the given indicators are not adequate to the total amount of these
metals in the organism (in toto), they convincingly demonstrate the
effectiveness of homeostatic regulation in relation to Na and K in
the most important biological media.
It is significant that we failed to find such a control in the
epidermis and its derivative (hair). The content of Na and K
in hair (median), which was measured using atomic emission
spectrometry in 10297 apparently healthy residents of Moscow
and Riga aged from 2 to 85 years (5160 men and 5137 women
without any symptoms of diselementosis), varied widely: sodium
- from 0.645 μg/g to 9240 μg/g; potassium - from 0.045 μg/g to
6505.1 μg/g [2].
Such a scatter of spectrometric data can be explained (at least
presumably) by the presence of two unrelated systems of Na/K
homeostasis: at the organismal and cellular (epidermis and its
derivatives) level. And since the measured parameters in each
of the autonomously working homeostatic systems should be
considered within the framework of only the system in which they
were obtained, the extrapolation of the hair spectrometry data to
the whole organism cannot be considered justified.
The very possibility of participation of a complex multilevel
system providing in toto homeostasis of Na and K (and, possibly,
other metals) in the MLH control of constantly (and rather rapidly)
renewing epidermis with its derivatives looks unrealistic.
Experience has shown that the “differences” (by several orders
of magnitude!) in the values of the concentration of Na and K in the
hair of the subjects did not in any way affect their well-being and/
or objective status. Along with it, any lethal risks are completely
excluded, unlike in toto situations, where such risks are very
relevant with much smaller changes in sodium and/or potassium
concentrations in plasma.
At the same time, the use of the main provisions of the theory
of self-organized criticality (SC) and spectrometric analysis helps to
explain some key events in the MLH of the epidermis. We are talking
about the emerging opportunity (according to hair spectrometry
data) to reliably diagnose the critical and subcritical phases in the
operation of the main membrane pumps for the transport of metals
in the epidermis - ATPases from the P-type family (and first of all,
Na+/ K+-ATPase).
The identification of these phases from the results of
spectrometry is available when constructing in a logarithmic scale
of Pareto plots, reflecting the probability density of the power-law
distribution (PDF). In this case, the critical state is characterized by
a power-law (fractal) distribution, which on a double logarithmic
scale takes the form of a straight line. The starting point of this
straight line - Сthr (the beginning of linearization on the Pareto plot)
means the beginning of the critical phase.
Here it is necessary to make an explanation that was not included
in the text of the mentioned article but seems important to warn
the reader of possible inaccuracy in the author’s interpretation of
the data obtained. The fact is that to find the Сthr point in our work
we used the results of atomic emission spectrometry of hair for
the content of Na and K obtained from 10,000 healthy individuals
(5,000 men and 5,000 women) at the age of 20-45 years. But as a
criterion for the distribution of subjects into two categories (with
subcritical and critical modes of operation of membrane Na+/K+
-ATPases), the found Cthr point on the Pareto graphs for Na and K
was used in individuals of different ages: from 2 to 86 years (947
healthy individuals and 954 liquidators of the Chernobyl accident).
The age discrepancy between the studied groups can, apparently,
affect the results of measuring each of the phases although it is
unlikely to significantly affect the conclusions of the authors.
Conclusion
In conclusion, I would like to offer clinicians some
recommendations on the use of metal spectrometry in such a
biosubstrate as hair. It is hoped that the proposed recommendations
will be in demand, since the capabilities and advantages of the
spectrometric analysis itself are becoming more and more popular
in the clinic.
A. What, first of all, should you pay attention to when analyzing
spectrometric data? First of all, you need to make sure that the
average values are calculated correctly and compared using
the methods of mathematical statistics that are suitable for this
purpose. As our investigations have shown, the distribution of
the results of spectrometry of all these metals does not obey
the “normal law” but is of a fractal nature. Therefore, standard
methods for calculating the average and it’s comparing
(Student) are unsuitable. In this case, special methods of
mathematical statistics are used (for example, the bootstrapmethod),
which “work” in the absence of normal distribution.
B. In addition, the value of measured indicators is closely related
to the sex and age of the subjects. In some metals (for example,
Ca, Mg, V, etc.), hair spectrometry revealed significant sex
differences in normal values (the “female norm” for Ca may
exceed the “male” one by more than two times). The age factor
plays an equally important role for the correct interpretation
of spectrometric analysis. According to our data, there are
significant age-related differences in the content of Na and K
in hair. Normal values (median) of these metals (bootstrapmethod)
in healthy people aged 2 to 9 years: Na - 324.9 μg/g;
K - 376.9 μg/g; age 20-49 years: Na - 99.9 μg/g; K - 47.1 μg/g;
age 60-85 years: Na - 293.9 μg/g; K - 121.4 μg/g [2]. A possible
relationship with age (preliminary data) was also found in
other metals (Ca, Al, Cd, Cr, Cu, Fe, Li, Pb, V, Zn). Therefore, a
reliable assessment of the results of spectrometry should
include mandatory consideration of gender and age.
C. What factors (other than those already mentioned) can
affect the value of the measured indicators? First of all,
these should include oxidative and nitrosative stress (as
evidenced by our own observations). In addition (according
to the literature), a significant effect on MLH can apparently
be exerted by carbonyl stress, which has an independent
significance in diabetes mellitus (regardless of the type of
diabetes) and/or as an aggravating addition to oxidative/
nitrosative stress in many clinical situations (inflammation,
cancer, cytodestructive conditions, infections, etc.). Therefore,
the increased production of reactive oxygen species (ROS)
and nitrogen (RNS) and, possibly, active carbonyl compounds
(ACC), such as glyoxal, methylglyoxal, malondialdehyde, etc.,
can be accompanied by quantitative shifts in the MLH of the
epidermis. It was found that these shifts are synchronous or
clustered. In other words, hyperproduction of ROS and RNS
leads to unidirectional quantitative changes in MLH, which can
be expressed by the following algorithm: [Na] ↑, [K] ↑, [Al] ↑,
[Cd] ↑, [Cr] ↑, [Cu] ↓ , [Li] ↑, [Fe] ↑, [Pb] ↑, [V] ↑, [Zn] ↓, where
the arrow indicates the direction of the quantitative shift
for each metal (increase ↑ or decrease ↓). This circumstance
determines the following tactics in obtaining and interpreting
spectrometric data.
D. In various clinical situations hair spectrometry can be used to
diagnose stress (oxidative, nitrosative, carbonyl?). At the same
time, a single analysis of the level of metal in the hair may prove
to be less informative and not indicative of the dynamics of the
process. At least two (or more) spectrometric measurements
with a time interval in acute clinical situations from several
hours to several days are required to establish a reliable
connection between MLH disorders and hyperproduction of
ROS, RNS or ACC (?). In the chronic course of the disease, this
interval can be measured in weeks (or months).
Conflict of Interests
None.
References
- Petukhov VI, Dmitriev EV, Baumane L Kh, Skalny AV (2021) Distinctive features of criticality in the work of membrane Na+/K+-ATPases. Acta Scientific Clinical Case Reports 2 (8): 84-90.
- Petukhov VI, Dmitriev EV, Baumane L Kh, Skalny AV, Lobanova Yu N (2016) Electrogenic metals in epidermis: relationship with cell bioenergetics. Insights in Biomed 1(2): 9-14.
