Biophysical-Semeiotic Evaluation of Acute Phase Proteins.
Technical and Practical Aspects.
“I acknowledge the valuable scientific advice provided to me by Prof.
Lars Retterstol, Institute of Medical Genetics, University of Oslo, by his
paper C-REACTIVE PROTEIN AS A MARKER OF CARDIOVASCULAR
DISEASE”
Introduction.
Bed-side evaluating Acute Phase Proteins (APP), including C Reactive Protein (CRP), is
nowadays possible by means of Biophysical Semeiotics. APP are numerous proteins, synthesized
by the liver; their bed-side evaluation has proved to be useful, from both diagnostic and prognostic
view-point, as allows me to state a long well-established “clinical experience. In addition, such as
original assessement represents an useful tool in research, and permits doctor to perform therapeutic
monitoring in a new, remarkable, and reliable way.
Acute Phase Proteins.
Acute Phase Proteins (APP), and primarily C Reactive Protein (CRP) are tremendous
valuable markers of disease activity (and responses to therapy) in tissue damaging, inflammatory,
infective, or neoplastic conditions (1). Automated CRP measurements were introduced in the early
1980s, but there was limited sensitivity and poor precision in the low range of CRP values, and
concentrations below 5-10 mg/L could not be detected. However, more sensitive CRP
measurements have uncovered new information on the development and progression of coronary
heart disease (CHD) (2).
The precise biological function of CRP is not fully understood, but its properties are
consistent with an important role in nonspecific defense mechanisms . It binds to a variety of
substances, including phosphocholin and thus recognizes several pathogens as well as phospholipid
constituents of damaged cells (3, 4). It activates, moreover, the classical complement system and
enhances the activity to phagocytic cells (1). CRP may initiate the elimination of targeted cells by
its interaction with both the cellular and humoral effector systems [6]. CRP may also induce
synthesis of cytokines and tissue factor in monocytes. It seems plausible that CRP has many
pathophysiologic roles in the inflammatory response (3), as allows to state Biophysical Semeiotics.
Median CRP values are typically 1-2 mg/L in healthy persons, double with age from 30 to
60 years, and tend to be higher in females than in males. It has long been known that CRP levels are
elevated in the presence of risk factors of CHD, including smoking, diabetes, obesity, and elevated
blood pressure (5-9) (See later on).
Among patients in stable phase after premature myocardial infarction (MI), CRP level was
the strongest predictor of both total and cardiac mortality. The effect of CRP is graded, and remains
over a long time of follow-up. In fact, CRP appears to be an even stronger predictor of cardiac and
total death than ejection fraction (10), which previously has shown to be the most significant
indicator of prognosis (11). CRP also predicts prognosis in patients with acute coronary syndromes.
Thus, CRP is associated with prognosis in patients in different stages of cardiovascular disease and
in healthy persons.
However, the underlying mechanisms that enhance low-grade inflammation are essentially
unknown, and several mechanisms are possible, according to numerous authors (12, 13, 14).
In my opinion, inflammatory event in pathogenesis of artheriosclerosis, in general, is not
primitive, but, if present, secondary, as I demonstrated in my site, HONCode, N° 233637,
www.semeioticabiofisica.it: “Biophysical-Semeiotic Arteriosclerotic Constitution” and
“Microcirculatory Theory of Arteriosclerosis”. (See later on).
As states Lars Rettersol, there is agreement among authors on some possible action
mechanisms, like the following:
(1) CRP may be a circulating marker of atherosclerosis. However, in a recent study no association
between angiographic findings and CRP was observed (14), but another and larger study concluded
otherwise (15). It was reported long ago that another marker of inflammation, erythrocyte
sedimentation rate, was associated to extend of coronary atherosclerosis (16).
(2) High levels of CRP may also indicate plaque-instability, reflecting activity of macrophages
within the plaque eroding the fibrous cap. CRP is a complement activator, and activated
complement may attack cells within the plaque, and thereby establish a self-sustaining autotoxic
mechanism leading to plaque instability and cardiac events (17)
(3) There are indications that CRP may promote larger cardiac injury in acute MI, perhaps through
activation through the complement system (18) implicating that high levels of CRP before the acute
MI worsen the outcome.
(4) CRP may promote blood clotting, possibly mediated through tissue factor [9] or other
thrombogenic proteins (19).
(5) Possibly, the effect of CRP on CHD may reflect infections, since CRP may be elevated by viral
and bacterial pathogens (20, 21) (See later on). Really, Biophysical Semeiotics, often but not in all
cases, as regards “only” the CAD, allowed me to corroborate these data, indicating surely that
elevated APP are a secondary, and not primitive facts, as other author demonstrated in according to
my results (20, 22).
6) CRP is elevated in acute MI, probably as a response to myocardial injury. In post-MI patients,
CRP may reflect infarction size, or long-term repair mechanisms or repair activity in the
myocardium, which may, or may not, be dependent of MI size (24).
(7) CRP may be a marker of an overall burden of risk factors or an unhealthy lifestyle.
Combinations of all these explanations are also possible.
Since CRP appears to be a strong predictor of prognosis, one might question whether CRP
should be used to screen the general population or be used as a tool for risk stratification of
cardiovascular patients in clinical settings (24). CRP has been reported to improve risk prediction in
general population screening (24) and special algorithms have now been proposed for such a
purpose, based on quintiles of CRP and TC: HDLC ratio.
Physicians may use CRP not only to evaluate prognosis, but also to evaluate the effects of
e.g. smoking and advocate smoking cessation. Furthermore, we have to remember the role played
by the assessment of CRP in the evaluation of smooking damages and beneficial effects due to
cessation, as well as in therapeutic monitoring, e.g., of some drugs, such as statins, which are also
antiinflammatory ones.
To summarize, to-day, although diagnostic and prognostic value of APP, briefly illustrated
above, we can not consider their high value neither in screening on large population, i.e., in the war
against CAD, nor in prognosis (e.g. of AMI), according to other authors (26), analogously to what
happened over last years as regards fibrinogen; both are markers of a low-grade inflammation, but
CRP is a more sensitive marker of inflammation and thus a better predictor of prognosis.
I agree completely with Lars Rettersol, who suggested me by its cited paper to write
present article, when states: “In addition, it has been observed that established
risk factors represent different risks in different persons as some
individuals remain healthy despite the presence of
hypercholesterolemia, hypertension, and even smoking, whereas the
same risk factors cause premature cardiovascular disease in others”.
In addition, the author states that “One is tempted to speculate whether
inflammation represents the key to this apparent paradox”, concluding as
follows: “In some (most) patients, these risk factors may cause an
increased inflammatory process and progress of atherosclerosis and
predisposition of thrombosis, while in a few patients, only minor
changes in the inflammatory response due to modifying genetic or
environmental factors. If so, the more than 300 "risk factors" of
cardiovascular disease available today can be reduced to only one risk
factor: inflammation”.
As I wrote in the cited site (“Biophysical Semeiotic Constitutions”) all possible “risk
factors”, by different pathogenetic action mechanisms, must necessarily act on a particular
“constitutional terrain” in order to provoke one or more of the most common and serious human
diseases, since genetic alterations, both “parenchymal” and “microcirculatory”, well located in a
precise biological system, represent the base of different constitutions, conditio sine qua non of the
deleterious effectes caused by “risk factors”, sometimes by means of inflammations.
I am going to demonstrate, from biophysical-semeiotic view-point, that the genetic
abnormality to produce APP, including CRP, more than normally, i.e. in healthy, takes part of
different “constitutions” , which predispose to DM, dyslipidaemia, arterial hypertension, rheumatic
diseases, arteriosclerosis, and malignancies.
In a few words, inflammation, revealed by increased production of APP and particularly
CRP in CAD, indicates exclusively the presence of one or more of some remarkable biophysicalsemeiotic constitutions, predisposing to diverse human disorders, which are most common and
serious. Abnormality of inflammatory response shows “clinically” the presence of one (or more) of
these constitutions, beeng a sign of them.
Acute Phase Proteins Synthesis: Biophysical-Semeiotic Work Hypotesis.
The synthesis of Acute Phase Proteins (APP), including CRP, takes place in the liver and is
stimulated by numerous products of damaged cells during infection, inflammation, malignancies,
a.s.o.
APP production increases rapidly in the course of infectious diseases, bacterial and viral in
origin, and, then, decreases slowly. Notoriously such substanses act as opsonine and activate both
synthesis of numerous cytochines and inflammation cells, taking a part of aspeciific
antiinflammatory response.
Hepatic production of APP is necessarily correlated with local microcirculatory
modifications, like associated microcirculatory activation, type I (See the site
www.semeioticabiofisica.it/microangiologia). In addition, as work hypotesis, I suspected the
presence, in the site of their production, of a “particular” stimulation of local hepatic receptors,
inflammatory in origin, analogously to the events of whatever inflammatory process: for example,
in case of rheumatic arthritis. In fact, under such as pathological conditions, Biophysical
Semeiotics allows to evaluate in “quantitative “ way APP synthesis.
As a consequence, I utilized the same stimulation, i.e., ungueal pressure, applied on
cutaneous hepatic dermathomeres (= cutaneous projection area of the liver), in healthy individual
without DM, hypertension, arteriosclerosis, rheumatic disorders, malignancies in their family
history, in supine position and psycho-physically relaxed, and assessed, at rest, “basal” behaviour of
hepatic-aspecific gastric reflex, type II, namely provoked by ungueal pressure (Fig. 1).
Fig. 1
Gastric aspecific reflex: in the stomach, both fundus and body are dilated, while antralpyloric region contracts, caused by ungueal pressure, applied upon lever cutaneous projection
area.
In healthy, after a latency time (lt) of 10 sec., appears the gastric aspecific reflex of 1-2 cm
in intensity, showing a duration > 3 sec. < 4 sec. and disappearing duration or differential latency
time, which preceeds the subsequent reflex, > 3 sec. < 4 sec., which parallells the fractal dimension,
when calculated in a sophysticated way (fractal dimension = 3,81), as now known (Fig. 2).
Fig. 2 indicates clearly the significances of reflex various parameters, in the reader’s
interest.
Fig. 2
Interestingly, in healthy, during “dynamic” evaluation, e.g., Restano’s manoeuvre (apnea
test, lasting only 5 sec., combined with boxer’s test) (See Glossary), lt lowers to 9 sec.: non
significant value from statistical view-point (Tab. 1).
By contrast, in every infectious diseases, both bacterial and viral, in rheumatic disorders,
and in malignancies, doctor observes early and characteristic modifications of parameter values:
reduced lt, < 5 sec., prolonged reflex duration > 4 sec. and shorter disappearing duration < 3 sec., in
relation to the seriousness of underlying disease, proving to be a reliable tool even in therapeutic
monitoring, as RESHS, antibody synthesis, diagram of tissue microvascular unit, simulated
sucking test, a.s.o. (See www.semeioticabiofisica.it).
Without discussing patho-physiological mechanisms of this reflex, wich are surely
fascinating, but they do not take any part of this paper, I emphasize the rigorous consideration of
Henle-Kock’s three parameters:
1) the presence of whatever disease, which stimulates APP synthesis, is always associated,
since early stage, with “pathological” parameter values of hepato-aspecific gastric reflex, type II;
2) reflex intensity parallels always disease seriousness;
3) therapeutic interventios, which favourably modify APP synthesis, contemporaneously
modify parametre values of type II hepato-aspecific gastric reflex.
At this point, I conjectured that APP synthesis, assessed with “ungueal” stimulation of
cutaneous lever-related receptors, could be in relation to subject’s constitution, in the sense that ,
besides a physiological response, described above (Tab. 1), I could observe, in apparently “health”
individuals, which really are involved by one (or more) biophysical-semeiotic constitution of
different seriousness, described in above-mentioned site, starting from the first two life decades, an
abnormal response of APP production, in the same way different in degree, at least during
“dynamic” manoeuvres.
On the other hand, it is well-known since a long time that diabetic react to a dangerous
infectious agents in a different way from what happens in non-diabetic patient, althoug the
abnormlities are different from case to case, as diabetic constitution itself.
A 45-year-long clinical experience allows me to state that the presence of “diabetic”,
”rheumatic”, “dislipidaemic”, “arteriosclerotic”, “hypertensive”, “oncological”, biophysicalsemeiotic constitution, either alone or associated with other(s), is always combined with
abnormalities of type II hepatic-aspecific gastric reflex, more or less intense: “basal” lt  9 sec.
(NN = 10 sec.) which lowers to < 5 sec. during Restano’s manoeuvre.
It follows that body response to the agents stimulating APP production in the lever, shows a
precise genetic component, always correlated with one (or more) particular biophysical-semeiotic
constitution, conditio sine qua non of disease onset, e.g., CAD, indicating clearly the real role
played by inflammation in arteriosclerosis pathogenesis, that is surely important, but secondary as
well as related to a special biophysical-semeiotic constitution, to which is linked in dependent way.
In other words, the altered, intense APP synthesis, under a large variety of pathological
conditions, is part of a (or more) singular “constitution” , and a sign of it.
From this original clinical view-point, Lars Rettersol’s compelling intuitions, referred
above, are corroborated and, moreover, enlightened by clinical evidence. Inflammation plays surely
an important and decisive role in disease onset, for example CAD, in many cases, because it is
always dependent by patient’s constitution, which defines both seriousness and type of disease.
BIOPHYSICAL-SEMEIOTIC EVALUATION OF ACUTE PHASE PROTEINS.
HEPATIC-ASPECIFIC GASTRIC REFLEX, TYPE II.
IN HEALTHY
BASAL VALUES: LT 10 SEC.; INTENSITY 1-2 CM.; DURATION > 3 < 4 SEC.;
DIFFERENTIAL LT >3 < 4 SEC. (fD 3,81)
DURING RESTANO’S MANOEUVRE: LT 9 SEC.; INTENSITY > 2 < 3 CM.; DURATA > 3
< 4 SEC.; TL DIFFERENTIAL >3 < 4 SEC. (fD < 3,81)
IN CASE OF ACUTE DISEASE: LT 3 SEC.; INTENSITY > 2 CM.
IN INDIVIDUALS WITH DIABETIC, RHUMATIC, HYPERTENSIVE,
ARTERIOSCLEROTIC, ONCOLOGICAL, A.S.O.
BASAL VALUES: LT < 10 > 5 SEC.; INTENSITY 2-2,5 CM.; DURATION  4 SEC.;
DIFFERENTIAL LT  3 SEC. (fD  3)
DURING RESTANO’S MANOEUVRE: TL  5; INTENSITY > 2 CM.; DURATION  4
SEC.; DIFFERENTIAL LT 3 SEC. (fD  3)
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