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Acid-Base Homeostasis:
Latent Acidosis as a Cause of Chronic Diseases
Jürgen Vormann, Thomas Goedecke
Institut für Prävention und Ernährung, DE-Ismaning
I
n the healthy human being, the blood
has a pH value of 7.4. Even slight
deviations from this value may lead to
s e v e r e disturbances in metabolism
which may even be life-threatening. It
is for this reason that the body`s exten-
sive buffer systems ensure that the
blood pH is maintained between the
very narrow limits of 7.37 and 7.43.
These buffer systems bind and neu-
tralize the additional protons (H
+
ions)
or hydroxide ions (OH
–
ions) respec-
tively associated with excessive acidity
or alkalinity and thereby prevent them
f rom immediate and marked influ-
ences on metabolism. In order to
maintain the optimal metabolic func-
tioning and there f o re the buff e r i n g
capacity on a long-term basis, the
organism is also dependent on the con-
stant regeneration of the buffer sys-
tems.
Physiological regulation of
acid-base homeostasis
What has been said above presuppos-
es precise regulation of the acid-base
homeostasis which involves many fac-
tors (Fig. 1). Apart from the buffering
characteristics of the blood and the
extracellular and intracellular com-
partments, the gas exchange in the
lungs and the excretion mechanisms of
the kidneys are essential components
of this regulatory system all of which
a re in functional equilibrium with
each other. The bicarbonate system is
of primary importance for maintaining
a constant blood pH, but plasma pro-
teins as well as the hemoglobin and
the phosphate buffer also play a role
Background: A prerequisite for the proper functioning of the enzyme-controlled metabolic
processes of the human organism is the regulation of pH both inside and outside of the cells. The
ratio of acids to bases is not only important for a healthy metabolism, it also determines the struc-
ture and function of proteins, the permeability of cell membranes, the distribution of electrolytes,
and
the function of connective tissue. Currently, long-term disturbances of the natural acid-base
homeostasis are receiving increasing attention as a risk factor for chronic diseases. Objective: To
determine whether there is causal evidence for the pathobiochemical effects of a low-grade
chronic metabolic (latent) acidosis and for the beneficial disease-modifying aspects of a well-bal-
anced acid-base homeostasis. Methods: The MEDLINE data base is systematically reviewed for
scientific literature since 1990 on latent acidosis and its impact on human health. Results:
A latent acidosis resulting from a gradual reduction of the buffer re s e rves, mainly due to nutritional
influences, does not produce major changes of blood pH because of compensatory mechanisms
through urinary acid excretion. However, there is causal evidence that this compensation, in the
long term, inevitably leads to loss of bone substance and impairs the structure and function of
the connective tissue. Conclusion: In the past, pH regulation was taken for granted in persons
not being severely ill and the required buffering capacity of the organism was accepted as being
virtually inexhaustible. But today latent acidosis resulting from a gradual reduction of the buffer
reserves is increasingly the focus of interest for the development and progression of chronic dis-
eases such as osteoporosis and rheumatoid disorders.
Key Wo rd s : Acid-base homeostasis, latent acidosis, osteoporosis, rheumatoid disorders, nutrition,
e v o l u t i o n
Säure-Basen-Haushalt:
Latente Azidose als Ursache chronischer Erkrankungen
Hintergrund: Die Regulation des pH-Wertes innerhalb und außerhalb der Zellen ist eine wesent-
liche Vorraussetzung für die Funktionsfähigkeit der enzymatisch gesteuerten Stoffwechselvor-
gänge unseres Organismus. Das Verhältnis von Säuren zu Basen ist nicht nur für einen gesunden
Stoffwechsel von Bedeutung, sondern entscheidet auch über die Struktur und Funktion von Pro-
teinen, die Permeabilität von Zellmembranen, die Verteilung von Elektrolyten sowie die Funktion
des Bindegewebes. Langfristige Störungen des natürlichen Säure-Basen-Gleichgewichtes finden
aufgrund des gegenwärtigen wissenschaftlichen Erkenntnisstandes als Risikofaktor für chroni-
sche Erkrankungen zunehmend Beachtung. Fragestellung: Lassen sich die pathobiochemischen
Auswirkungen einer geringgradigen chronischen metabolischen (latenten) Azidose und die positi-
ven gesundheitlichen Aspekte eines ausgeglichenen Säure-Basen-Haushalts kausal belegen?
Methoden: Systematische Auswertung der wissenschaftlichen Literatur in der MEDLINE Daten-
bank ab dem Jahr 1990 über die latente Azidose und deren Einfluss auf die Gesundheit. Er
geb-
nisse: Eine latente Azidose als Folge einer schleichenden Verminderung der Pufferreserven, über-
wiegend bedingt durch Ernährungseinflüsse, ruft aufgrund der Kompensation durch die Säu-
reausscheidung über die Nieren keine wesentlichen Veränderungen des Blut-pH hervor. Aller-
dings führt diese Kompensation auf lange Sicht unausweichlich zu einem Verlust von Knochen-
substanz und beeinträchtigt die Struktur und Funktion des Bindegewebes. Schlussfolgerung: In
der Vergangenheit wurde die pH-Regulation bei Personen, die nicht ernsthaft erkrankt sind, als
Selbstverständlichkeit aufgefasst und die hierzu erforderliche Pufferkapazität des Organismus als
beinahe unerschöpflich erachtet. Heute wird zunehmend erkannt, dass die latente Azidose als
Folge einer allmählichen Abnahme der Pufferreserven für die Entstehung und den Verlauf chroni-
scher Erkrankungen wie z.B. Osteoporose und Rheuma von Bedeutung ist.
S c h l ü s s e l w ö rt e r : S ä u re-Basen-Haushalt, latente Azidose, Osteoporose, rheumatische Erkrankun-
gen, Ern ä h run g, Evolution
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as H
+
or OH
–
scavengers. The highly
rapid responsiveness of the buffer sys-
tems produces an extremely fast and
constant regulation of the blood pH.
Apart from water, transient carbon
dioxide – the intermediate pro d u c t
from the protonation of bicarbonate
(HCO
3
–
) – is produced by the dissocia-
tion of carbonic acid; it is expired via
the lungs and, as a result, H
+
ions are
effectively eliminated. However, since
HCO
3
–
is also removed at the same
time, net acid excretion does not take
place. Even though acute acidosis can
usually be avoided by carbon dioxide
expiration, the buffer systems of the
kidneys are primarily responsible for
the net excretion of the H
+
i o n s
released from the breakdown of various
acids.
This excretion is necessary because
the production of protons (e.g. via
metabolizing sulphur-containing amino
acids from protein) from a normal
mixed diet exceeds the absorption of
alkaline substances. In the modern
diet, mainly the proportionately high
consumption of protein compared with
that of base-supplying fruit and veg-
etables contributes to the daily acidifi-
cation of the body. A particular exam-
ple of acidification is that from imbib-
ing phosphoric acid-containing bever-
ages. Fasting (i.e. reducing body weight
by not eating) increases the acidifica-
tion of the body via the increased for-
mation of keto acids from the break-
down of fatty acids, and so does the
i n c reas ed production of lactic acid
under anaerobic conditions as the end
p rod uct of glycolysis during sport s
activities.
With regard to the buffering of H
+
ions, of major importance are those
alkaline vegetable substances in the
form of metabolizable organic anions
that can neutralize the acid produced
from protein metabolism. During the
dissociation of these salts, org a n i c
anions are released which can then –
depending on the dissociation constant
of the acid group – accept H
+
ions. The
organic acids produced are neutrally
metabolized to water and carbon diox-
ide (CO
2
) and ensure in this way that
p rotons are eliminated from the
organism. As is shown for the example
of sodium citrate (Fig. 2), the remain-
ing cations (e.g. Na
+
) are available for
reabsorption from the primary urine
in the kidney in exchange for H
+
ions.
By this means, the charge neutrality is
maintained and acid is eliminated
from the body. It can thus be seen that
the level of intake of organic anions
represents a major factor in regulating
acid-base homeostasis.
Definition of latent acidosis
and its manifestations
Compared with the clinically rather
r a r e manifestation of re s p i r a t o ry or
m e t a bolic acidosis, which is character-
ized by a decrease in the blood pH,
latent acidosis is much more commonly
observed. In most cases, there is a
slight shift of the blood pH in the acid
direction within the normal range and
the total buffering capacity of the
blood is reduced. The term “latent”
refers to a chronic condition which is
without acute symptoms and is clini-
cally detectable only by determining
the intracellular and extracellular
buffer capacity and the renal net acid
excretion.
It is mentioned here that latent aci-
dosis affects a wide cross-section of
the population. The cause of increased
acidification is, above all, the high pro-
tein content in food which, when cou-
pled with the declining renal function
associated with increasing age, leads
to latent acidosis
[1]. With increasing
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Fig. 1. Regulation of the acid-base homeostasis.
Fig. 2. Function of organically bound minerals in the elimination of acids as shown for
the example of sodium citrate.
age, the ability of the kidneys to excre t e
acids progressively decreases [2, 3]. As
is shown in Fig. 3, the blood pH
declines within the normal range over
the years, but at the same time the
concentration of plasma bicarbonate
buffer bases also decreases.
This in turn not only results in an
i n c reas ed consumption of buff e r i n g
minerals from the bone reservoir, but
also in detrimental effects on various
metabolic functions such as the
increased muscle breakdown which is
frequently observed in senior citizens
[3]. The age-related renal functional
decline together with a constantly high
protein intake exacerbates latent aci-
dosis and its harmful influences on
health.
Compensation mechanisms
of latent acidosis
Nowadays, the pathobiochemical eff e c t s
of latent acidosis on osteoporosis, dia-
betes mellitus, hyperuricemia, gout, or
on restricted renal function are
undisputed. These links were ultimate-
ly recognized because of the very eff i-
c i e n t homeostatic counter-regulation
of the organism in maintaining the
bicarbonate and proton concentrations
and there f o r e the pH value of the blood.
The regulation mechanisms have
been partially explained in re c e n t
years [4]. The adaptation mechanisms
of the kidney play an essential role in
compensating diet-induced latent aci-
dosis. They are schematically depict-
ed in Fig. 4. There are four ba
sic mech-
a n i s m s that compensate for latent aci-
dosis.
Increased excretion of
ammonium ions (NH
4
+
)
Ammonia (NH
3
) – which is produced in
the renal tubular cells and freely dif-
fuses through membranes – combines
with H
+
ions in the primary urine to
form ammonium (NH
4
+
) ions which
can hardly diffuse back and which are
therefore excreted with the urine (pro-
ton trapping). Consequently most of
the renal acid is excreted bound to
NH
3
. This latter product is formed in
the tubular cells from the breakdown
of the nitrogenous amino acid gluta-
mine. With acidosis, the activity of the
glutamine-degrading enzymes (gluta-
minase, glutamine-dehydrogenase etc.)
is increased. Accordingly, there is an
increased consumption of glutamine
and subsequently of other nitrogen-
supplying amino acids. Thus, mild
latent acidosis also leads to increased
activity of the protein-degrading sys-
tems via the production of ubiquitin
and C2/C3 proteasoms in the muscular
system with a corresponding loss of
myoprotein. By increasing the intake
of bases, the loss of nitrogen caused by
mild latent acidosis could be prevented
in postmenopausal women [5].
Increased secretion of protons
(H
+
) in the renal tubules
Even with mild acidosis, the quantity
and activity of the Na
+
/ H
+
ion exchanger
in the kidney is increased, resulting in
increased excretion of H
+
ions with
simultaneous Na
+
reabsorption.
Reduction of
urinary citrate excretion
With acidosis the relative reabsorption
of critrate
3–
(the trivalent negatively
charged anion of citric acid) from the
primary urine is increased. Compensa-
tion occurs by the following mecha-
nism: the absorption of citrate
3–
in the
tubular cells occurs mainly in the pro-
tonated form, i.e. H-citrate
2 –
. The
activity of the citrate transporter is
therefore increased with reduced pH.
Intracellularly, citrate
3–
is converted
by the acceptance of additional pro-
tons to
uncharged citric acid, which is
then pH-neutrally broken down into
carbon dioxide and water. By the
absorption of one molecule of citrate
3–
from the primary urine, 3 H
+
ions can
therefore be eliminated. As a result,
the concentration of citrate in the pri-
m a ry urine decreases (see Fig. 4) .
However, citrate is essential for com-
plexing calcium ions (Ca
2+
). The lack
of formation of soluble calcium-cit-
rate-complexes increases the urinary
concentration of free Ca
2+
ions and
therefore the availability of calcium to
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Fig. 3. Relationship between blood pH and
plasma bicarbonate concentration and age
(modified from [2, 3]).
Fig. 4. Compensation mechanisms for latent acidosis (modified from [4]).
Urine Kidney Blood Bone
1. NH
4
+
formation ↑
2. H
+
secretion ↑
3. citrate re a b s o r p t i o n ↑
4. Ca
2+
reabsorption ↓
1. [NH
4
+
] ↑
2. [H
2
PO
4
-
] ↑
3. [Ca
2+
] ↑
4. [H
+
] ↑
5. [citrate
3-
]↓
1. Ca
2+
/PO
4
3-
release↑
2. osteoblast activity ↓
3. osteoclast activity ↑
blood pH ↓
[HCO
3
-
]↓
Protein
break down
Muscle
7.3
6
7.3
7
7.3
8
7.3
9
7.4
0
7.4
1
26
24
22
20
f o r m renal calculi, e.g. with oxalic acid.
Increased release of minerals
from the bones
On the one hand, mild acidosis leads to
the removal of minerals from the bone
matrix; on the other hand, acidosis
results in an increase in the activity of
the bone-decomposing osteoclasts and
inhibition of the activity of the bone-
forming osteoblasts (see Fig. 10). All in
all, increased renal excretion of Ca
2+
ions takes place with the consequence
of the increased risk of formation of
renal calculi, as described above.
Effects of latent acidosis
on calcium and bone
metabolism
Epidemiology and
dietary implications
With experimental acidosis, first a
reduction of the blood buffering capac-
ity occurs, then, with further increase
of acid load a reduction of the intracel-
lular buffering capacity and a strain on
the buffering capacity of bone occurs.
And finally, with increasing acid load
buffering is achieved by the release of
minerals from bone [6]. This and com-
parable investigations led already in
the Sixties to the hypothesis, that one
of the significant causes of osteoporo-
sis is a high dietary acid load [7].
Numerous epidemiological studies
are available on the obvious relation-
ship between the type of diet and the
development of osteoporosis. The
influence of a vegetarian diet on bone
mineral density is based on the signif-
icant effect of dietary content of acid
and base: a higher base content is cor-
related with a higher bone mineral
density [8]. A comparative study on
omnivorous and vegetarian women [9]
showed that a high proportion of base
generating foodstuffs leads to a clearly
improved calcium balance in vegetari-
ans. In spite of equal calcium intake in
both groups, the women who consumed
a mixed diet showed not only a signifi-
cantly higher excretion of acid but also
a significantly higher excretion of cal-
cium. For premenopausal women a
correlation was shown between the
intake of alkaline foods and bone min-
eral density [10]. Although the intake
of alkaline food components (especial-
ly potassium and magnesium) and the
high consumption of fruit and vegeta
-
bles were correlated with an increased
bone mineral density in a study on
elderly subjects, this was not the case
for the calcium content of the con-
sumed food [11]. No associations with
other food components, e.g. the cal-
cium intake or the total caloric intake,
were found in this study.
Recent epidemiological studies on
the nutritional effects on bone loss
during menopausal transition demon-
strated that with decreasing endoge-
nous acid production femoral bone
mineral density of pre- and perimeno-
pausal women significantly increased
[12], see Fig. 5.
Another epidemiological study
showed the beneficial effect of cal-
cium, alcohol, and fruit and vegetable
intake and the detrimental effect of
fatty acids. The authors conclude that
although menopausal status and hor-
mone replacement therapy dominate
women's bone health, diet may influ-
ence early postmenopausal bone loss
with fruit and vegetable intake pro-
tecting against premenopausal bone
loss [13]. These findings are confirmed
by the results of a study which investi-
gated the relationship between dietary
potassium and protein intake, net
endogenous acid production and
potential renal acid load and markers
of bone health. Low dietary potassium
intakes and high dietary estimates of
net endogenous acid production were
found to be associated with low bone
mineral density at the femoral neck
and lumbar spine in premenopausal
women (Fig. 6) and increased markers
of bone resorption in post-menopausal
women [14].
On the whole, the epidemiological
data indicate a correlation of the
intake of alkaline acting-substances
from fruits and vegetables and the cor-
responding dietary acid load over the
years and their effects on calcium and
bone metabolism from the viewpoint of
osteoporosis.
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Fig. 5. Mean (± SEM) bone mineral density of pre- and perimenopausal women by
quartile of net endogenous non-carbonic acid production (NEAP). *Significantly different
from quartile 4, p<0.04. Modified from [12].
Confirmation
by intervention studies
I n t e rvent ion studies largely confirm
the physiological effects of latent aci-
dosis. In animal experiments it was
shown that due solely to a high-protein
diet, the bone formation in young rats
was impaired [15]. Another study (see
Fig. 7) shows that an excess acid load
was artificially caused by an increase
of the protein intake [16]. As expected,
increased renal net acid excretion (as
the sum of ammonium and titratable
acids) and calcium excretion were first
o b s e rved. However, because of the
concomitant intake of sodium bicar-
bonate as a base supplier, a negative
calcium balance could be prevented
and the protein-induced over-acidifi-
cation of the organism was neutral-
ized. The positive effects of a high
intake of base-forming substances
could also be proved in intervention
studies with postmenopausal women:
i n c reased alkaline intake bro u g h t
about both a reduction in the break-
down of bone and an increase in bone
formation [17]. Thanks to a reduction
of the protein intake, the calcium
excretion and therefore the risk of
renal calculi could be reduced in
h y p e rcalciuric patients [18]. In a
p l a c e b o - c o n t r olled study comparing
treatment with alkaline minerals to a
placebo group for almost all syn-
dromes involving the gastrointestinal
tract, musculoskeletal system, cardio-
vascular system, skin, and a tendency
to become easily exhausted, a consid-
erable improvement of the symptoms
was shown [19]. Moreover, laboratory
parameters (e.g. acid excretion, serum
c h o l e s t e r ol) were significantly impro v e d
by means of the
alkaline therapy.
Treatment with alkaline salts such
as potassium citrate is even able to
reduce bone resorption. This effect of
potassium citrate supplementation on
bone metabolism was investigated in
46 postmenopausal women with low
bone density. One group received a
3-month course of potassium citrate
supplementation (0.08 – 0.1 g/kg body
weight daily), another group served as
control. Evaluation of electrolyte and
acid-base homeostasis-related para-
meters, and markers of bone turnover
and of renal function showed a signifi-
cant decrease in net acid excretion
only upon citrate supplementation.
Moreover, urinary excretion of bone
resorption markers decreased thus
indicating that citrate ingestion posi-
tively affects bone health [20]. The
equimolar replacement of dietary sodi-
um chloride and potassium chloride
with alkaline sodium and potassium
bicarbonate under metabolic homeosta-
sis conditions, thus neutralising dietary
acid load, not only resulted in signifi-
cant calcium retention and reduced
renal excretion of bone markers but
also decreased mean daily plasma cor-
tisol and urinary excretion of tetra-
h y d ro c o r tisol [21]. Other endocrine
factors relevant to bone such as para-
thyroid hormone or vitamin D were
not affected. There f o re, mild metabolic
acidosis may be associated with a state
of cortisol excess. These acidosis-
induced increases in cortisol secretion
and plasma concentration may play a
role in mild acidosis-induced alter-
ations in bone metabolism as well.
Dieting and Fasting
Dieting and fasting are critical to
changes of acid-base homeostasis. For
example,
solely because of the intake
of sodium bicarbonate, the calcium
release from bone in young women
who had developed ketoacidosis as a
result of fasting could be prevented
[22]. Generally speaking, modern diets
contribute to an increase in metabolic
acidosis and to greater bone loss as
demonstrated for low-carbohydrate,
h i g h - p r otein diets (Atkins). Consumption
of such a diet for six weeks may in fact
help an individual to lose weight, but it
considerably increases acid load and
results in latent acidosis with
increased risk of kidney stone forma-
tion, negative calcium balance, and
increased risk of bone loss, as demon-
strated in Fig. 8 [23]. Table 1 illus-
trates the dietary scheme applied for
three different phases.
Is animal or vegetable protein
detrimental to bone health?
Judging from the most recent studies,
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Fig. 6. Mean (± SEM) bone mineral density at the femoral neck and lumbar spine with
increasing quartiles of energy-adjusted potassium intake for premenopausal women
(n=336). *Significantly different from quartile 1, p<0.01. Modified from [14].
food protein from different sources
seems to have different effects on bone
metabolism. Elderly women who have
a high proportion of animal protein in
their diet showed a more rapid loss of
bone density and a higher risk of hip
fractures than women with a low pro-
portion [24]. In the latter group (low
proportion of animal protein), it was
found that fewer women sustained a
hip fracture during the observation
period of 7 years. Animal foods contain
p r edominantly acid-forming substances
whereas protein in vegetable foods is
accompanied by base-forming sub-
stances.
The protective function that an
increased consumption of vegetables
as opposed to animal protein may have
has also been confirmed in interna-
tional studies. The incidence of hip
fractures differs in the populations of
different countries, and it is directly
correlated with the level of consump-
tion of animal protein of the different
cultures. Analysis of the data on the
incidence of hip factures in 33 coun-
tries in relation to the respective coun-
try-specific characteristics of the per
capita consumption of animal and veg-
etable foods (Fig. 9) showed that the
incidence of hip fractures is the lowest
in countries with a low intake of ani-
mal protein [25].
H o w e v e r, latest studies with childre n
indicate that protein consumption is
not generally detrimental to bone
health because in children long-term
dietary protein intake appears to act
anabolically on diaphyseal bone
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Tab. 1. Composition of normal diet, severely carbohydrate-restricted induction diet and
moderately carbohydrate-restricted maintenance diet. Modified from [23].
(g/day) Duration Carbo- Protein Fat Body weight
(weeks) hydrates (kg, n=10)
Normal 2 285 81 90 81.3
Induction 2 19 164 133 78.4
Maintenance 4 33 170 136 77.2
Fig. 7. Renal acid and calcium excretion with different protein intakes [g/day] with and
without sodium bicarbonate substitution [70 mEq/day] (modified from [16]).
Fig. 8. Effect of low-carbohydrate, high-protein diet (Atkins diet) on renal net acid excretion, renal calcium excretion and serum osteocal-
cin. Patients had been on a normal non-weight-reducing diet, then a severely carbohydrate-restricted induction diet for 2 weeks, after which
they followed a moderately carbohydrate-restricted maintenance diet for 4 weeks as depicted above (n=10). Modified from [23].
strength during growth. This may at
least partly be negated if the dietary
potential renal acid load is high, i.e. if
the intake of base-forming minerals,
as provided by a high consumption of
fruit and vegetables, is low. Children
with higher dietary potential re n a l
acid load (PRAL), however, had signifi-
cantly lower bone mineral content and
l o n g - t e r m calcium intake was not
associated with any bone variable.
Protein and alkalinising minerals are
thus increasingly described as playing
a major role in influencing bone status
in children and adolescents [26].
Mechanisms of the effects of acid
on bone cell function
The homeostasis for the maintenance
of a stable physiological pH environ-
ment often functions only at the
expense of the bone mineral content
because latent acidosis causes the
release of calcium from bone, thereby
b u f fering the additional pro t o n s .
Metabolic acidosis first stimulates the
physicochemical release of minerals
(decrease of the sodium, potassium,
carbonate, and phosphate content of
bones) and subsequently the cell-
mediated absorption of bone, as is
schematically depicted in F i g . 1 0 .
Acidosis results in an increase in the
activity of bone-decomposing or re s p e c-
tively bone-resorbing cells (osteoclasts)
and inhibition of the bone-form i n g
cells (osteoblasts).
Genes that regulate the
early “imme-
diate reaction” of the osteoblasts are
inhibited as are genes that control the
formation of bone matrix; gene inhibi-
tion leads to an overall reduction of
bone remodelling and form a t i o n .
Several in vitro studies with artificially
cultured bone cells confirmed their
characteristics as potent acid buffers
[27].
Figure 11 shows the dependence of
the net calcium flux of cultured bone
cells on the pH value of the surround-
ing medium. With a physiologically
acidic pH value below 7.4, calcium
flows out of the bone cells into the
medium, whereas a net absorption of
calcium was only detectable with a pH
value above 7.4.
G r owth and maturation of the osteo-
clasts is dependent on the interplay of
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Fig. 9. Worldwide incidence of hip factures (modified from [25]).
Fig. 10. Schematic diagram of the effects of latent acidosis on bone (modified from [27]).
a number of factors. One of the expla-
nations of the mechanisms of latent
acidosis on bone cell function is the
induction of osteoblastic prostaglandin
synthesis, which is activated by meta-
bolic acidosis and is followed by the
induction of a “receptor activated
NFκB ligand” (RANKL). This increase
in RANKL is expected to augment osteo-
clastic bone resorption by interaction
with the osteoclastic cell-surf a c e
receptor RANK as shown in Fig. 12.
The RANKL/RANK interaction not only
initiates a differentiation cascade of
pre-osteoclasts to osteoclasts, that cul-
minates in mature bone-re s o r b i n g
osteoclasts, but also increases the
resorptive capacity and survival of
osteoclasts [28]. This acidosis-induced
increase in RANKL is expected to aug-
ment osteoclastic bone resorption and
offers an appropriate explanation for
the increase in cell-mediated net cal-
cium efflux as described above.
Finally, thanks to the mechanisms
of compensation dietary-induced latent
acidosis does not provoke any signifi-
cant changes of blood pH but the com-
pensation inevitably consumes the
b o d y ’s re s e r voir of buffering sub-
stances. When excess intake of animal
protein and deficient dietary base sup-
ply persists for a longer time this will
have a negative impact on bone mass.
The undoubted positive influence of a
diet rich
in fruit and vegetables can be
explained not only by a high intake of
micronutrients and secondary herbal
ingredients but also by the positive
effects of an adequate base supply.
Effects of latent acidosis on
connective tissue function
Connective tissue is an important tran-
sit pathway for metabolic pro d u c t s
such as oxygen, carbon dioxide, nutri-
ents, electrolytes, water, acids and
bases. Even slight changes of the blood
pH lead to a change in the physico-
chemical characteristics of the proteo-
glycans, the branched protein-saccha-
ride constituents of connective tissue.
These proteoglycans directly exchange
with the extracellular fluid.
Proteoglycans are composed of a
p r otein component and a glucosamino-
glycan component, which contains a
multitude of negatively charged func-
tional groups (e.g. sulphate residues
R ~ O - S O
3
–
). This negative charge enables
the binding of water molecules which
contribute to the elasticity and flexibil-
ity of the connective tissue. In latent
acidosis the negative charge of the sul-
phate residues is diminished and the
water binding capacity is decreasing
t h e reby reducing the elasticity and
flexibility of the connective tissue.
In cartilage as well, proteoglycans
with the hyaluronic acid molecules
that are bound to them represent a
h i g h - m o l e c u l a r-weight polyanionic
complex that forms the import a n t
compressible component of cartilage
because of the high water- b i n d i n g
capacity [29]. The water-binding capac-
ity of the extracellular matrix proteins
is very much determined by the degree
of dissociation of the functional acid
residues whose dissociation is again
highly pH-dependent. Acidosis of the
synovial fluid therefore decreases car-
tilage elasticity due to reduced water
binding. Effects
of latent acidosis on
the function of cartilage can be
explained in this way. At present, how-
e v e r, the complex stru c t u re of the
extracellular matrix does not allow
direct measurement of the function of
c a r tilaginous tissue with diff e r e n t
d e g ree s of dissociation. In patients
with rheumatoid arthritis the pH of the
knee joint’s synovial fluid is signifi-
cantly more acidic compared to the
normal range (pH 7.4 – 7.8), as shown
in Fig. 13 [30]. Consequently, acidosis
encourages joint cartilage abrasion by
mechanical stress that promotes the
vicious circle of deformation and
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Fig. 11. Effect of medium pH on the net cal-
cium flux in cultured bone cells. A positive
value shows a net calcium flow out of the
bone cells into the surrounding medium, nega-
tive values indicate net calcium influx (modi-
fied from [27]).
Fig. 12. Scheme of acidosis induced activation of RANKL/RANK interaction initiating the
differentiation cascade of pre-osteoclasts and increasing bone resorptive capacity and
survival of osteoclasts (modified from [28]).
Net calcium flux
(nmol/bone/3h)
Initial medium pH
inflammation. Acidosis might also
impair the filtration effect of the con-
nective tissue which may, in turn ,
additionally contribute to a deteriora-
tion in the nutrient supply of this poor-
ly perfused tissue. Finally the whole
locomotor system is involved because
of acidosis-induced impairment of the
ligaments and tendons.
Patients with chronic low back pain
without radicular involvement benefit-
ed from a 4-week supplementary diet
therapy by taking alkaline minerals:
both the pain as well as the physical
mobility improved significantly (see
Fig. 14), and the consumption of non-
s t e roidal, anti-inflammatory dru g s
(NSAID), which may cause severe side
effects when applied chronically, could
be clearly reduced [31]. Indeed, long
term balancing of acids and bases is
required for a complete regeneration
of the connective tissue and to notice-
ably relieve the chronic pain.
In a recent study, patients with
rheumatoid arthritis of at least two
years’ duration were shown to have
benefited from alkaline mineral sup-
plementation (see Fig. 15). At the end
of a 12-weeks study there was a signif-
icant decrease in disease activity score
(DAS-28) and in pain level measured
on a visual analogue scale (VAS) only
in the group supplemented with 30 g/
day of an alkaline food supplement
(Basica Vital
®
) compared to the control
group. Moreover, the steroid or NSAID
medication could be reduced with
alkaline supplementation whereas no
reduction of medication was consid-
ered to be possible for the control
group [32].
Another important impact on acid-
base homeostasis with long-term eff e c t s
on the functions of the connective tis-
sue occurs with chronic intake of pro-
ton pump inhibitors for the treatment
of gastroesophagea
l reflux. After meals
the parietal cells produce hydrochloric
acid to enable the digestion of foods.
At the same time bicarbonate is gener-
ated and transferred into the blood
stream from where it afterwards is
transported via the bile ducts into the
intestine to neutralize or alkalize the
gastric mash. This closed system does
not exert any net effect on acid-base
homeostasis, but acts as a kind of tem-
poral effect reflected by the “alkaline
floods” after each meal. These alkaline
floods provide an important physiolog-
ical process for removing the acids
bound to sulphated residues of con-
nective tissue proteoglycanes. Chronic
intake of proton pump inhibitors such
as omeprazol interfere with this sys-
tem and may suppress the essential
“purification process”.
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Fig. 13. Mean H
+
concentration in the synovial fluid from the knee joints of patients with
different forms of arthritis (modified from [30]).
Fig. 14. Effects of alkaline mineral supplementation on patients with chronic low back
pain. Arhus low back pain rating scale before and after supplementation with Basica
®
(n=82). Modified from [31].
Arhus low back pain rating scale (ARS)
before and after supplementation with Basica
®
Evolutionary aspects of
acid-base homeostasis
There is a growing awareness that the
profound changes in the environment
including diet and other life-style con-
ditions that began with the introduc-
tion of agriculture and animal hus-
b a n d r y approximately 10,000 years
ago, occurred too recently on an evo-
lutionary time scale for the human
genome to adjust. In conjunction with
this discordance between our ancient,
genetically determined biology and the
nutritional, cultural, and activity pat-
terns of contemporary Western popu-
lations, many of the so-called diseases
of civilization have emerged. In partic-
ular, agriculture and food-processing
p ro c e d u r es introduced during the
Neolithic Period and during the
Industrial Period fundamentally altere d
crucial nutritional characteristics of
the diets of our ancestors: in addition
to changes in the glycemic load, fatty
acid composition, macronutrient com-
position, micronutrient density, sodi-
um-potassium ratio, and fibre content,
considerable changes have taken place
in the acid-base homeostasis. Comparison
of the estimated net endogenous acid
production (NEAP) from 159 retro-
spective ancestral preagricultural diets
with contemporary diets clearly demon-
strates that 87% were net base-pro-
ducing with a mean NEAP of –88 ± 82
meq/day [33].
The average contemporary American
diet provides an acid surplus of 48
meq/day and is characterized by an
imbalance of nutrient precursors of
hydrogen and bicarbonate ions there-
by
inducing a lifelong, low-grade
pathogenically significant systemic
metabolic acidosis. The historical shift
from negative to positive NEAP was
a c c o u n t ed for by the displacement of
highly alkalising plant foods in the
ancestral diet by cereal grains and
energy-dense, nutrient-poor foods in
the contemporary diet – neither of
which are net base-pro d u c i n g .
Therefore the evolutionary collision of
our ancient genome with the nutrition-
al qualities of recently intro d u c e d
foods may underlie many of the chro n i c
diseases of Western civilization [34].
Further research fields
related to acid-base
homeostasis
In sportsmen and sportswomen, fre-
quent lactate acidosis increases the
susceptibility to physical injury. In con-
trast, it is suggested that an adequate
base supply may have a beneficial
impact on performance by delaying
the onset of lactate acidosis but also by
avoiding physical impairment. Muscle
activity during sports performance is
in fact known to be associated with an
increase in both intra- and extracellu-
lar proton concentration. It is known
that alkaline sodium citrate ingestion
could reduce plasma proton concen-
tration and improve physical perfor-
mance [35, 36, 37].
Extracellular pH affects mineral
cation flux through cell membranes as
well. It seems that there is a strong
correlation between interstitial proton
concentration and the potassium
release from muscle cells during exer-
cise since potassium efflux is regulated
by voltage-dependent K channels and
pH-dependent K
ATP
channels. Potas-
sium efflux and accumulation in the
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Fig. 15. Percent change of disease activity score DAS-28 (left) and percent change of VAS pain index (right) of rheumatoid arthritis patients
(*p<0.05, **p<0.01). Modified from [32].
interstitium is not only important for
muscle function but also for the develop-
ment of fatigue resulting from exer-
cise. Microdialysis measurements have
recently demonstrated that sodium
citrate ingestion (300 mg/kg body
weight) reduces the exercise-induced
interstitial acidosis in human skeletal
muscle (Fig. 16) [38].
It was also shown by the latter
authors that this reduction of H
+
ion
concentration was associated with a
reduced interstitial accumulation of
potassium during muscle activity.
These results accordingly suggest a
delayed onset of muscle fatigue and
sustained muscle perf o r mance by
alkaline sodium citrate ingestion prior
to exercise in sports.
Of considerable interest was the
finding, in a study on 42 boys [39], of a
significant positive correlation between
the pH in the brain and the intelligence
quotient (IQ), i.e. the lower the actual
acid concentration in the brain, the
higher the IQ.
Conditions representing physiologi-
cal acidosis in vitro induced the aggre-
gation of human Ab amyloid proteins
( A b ) [40]. Metal ions such as copper,
zinc and iron are enriched in the amy-
loid plaques in Alzheimer's disease
and unlike other biometals tested at
maximal biological concentrations,
marked copper-induced aggregation of
Ab emerged as the pH of the sur-
rounding solution was lowered from
7.4 to 6.8. The reaction was completely
re v e r s i b l e with eit
her chelation or
alkalinization. Since a mildly acidic
environment together with increased
copper and zinc concentrations are
common features of inflammation, it is
suggested that Ab aggregation by
these factors may be a response to
local injury and that metabolic acido-
sis may also play a role in the develop-
ment of Alzheimer’s disease.
The acid-base homeostasis depen-
dent modulation of cortisol output may
influence the risk of insulin resistance
syndrome. This hypothesis appears to
be consistent with previous epidemio-
logical reports correlating high potas-
sium consumption, or a high intake of
fruits and vegetables, with a reduced
risk for diabetes and coronary disease.
Metabolic acidosis is known to pro-
mote renal acid excretion by the
induction of ammonia-generating glut-
aminase and other enzymes in the
renal tubules (see earlier: Compensation
mechanisms of latent acidosis). This
process is also strongly correlated with
i n c reased cortisol and aldostero n e
p r oduction. Since cortisol promotes the
development of visceral obesity, and
has a direct negative impact on insulin
function throughout the body, even a
modest sustained up-regulation of cor-
tisol production may have the potential
to increase the risk of insulin resis-
tance syndrome and type 2 diabetes
[41]. Future prospective epidemiology
should assess whether the estimated
acid-base homeostasis of habitual
diets correlates with the risk of insulin
resistance syndrome and diabetes.
Conclusion
To what extent the diet can affect the
acid–base homeostasis has been the
subject of controversy for many years.
Acute acidosis or alkalosis cannot be
produced by the consumption of cer-
tain foods. Howeve
r, the pathobio-
chemical effects of latent acidosis on
impaired renal function, diabetes mel-
litus, hyperuricemia, or gout are
undisputed. Based on new scientific
findings, causal evidence has also now
been furnished for the positive effects
of a well-balanced acid-base equilibri-
um empirically established in natur-
opathy. Although diet-induced latent
acidosis does not produce major
changes in the blood pH because of the
compensation mechanisms of the kid-
ney, this compensation inevitably leads
to the consumption of endogenous
buffer reserves and, therefore, pre-
dominantly to a loss of bone substance
if the increased acidification caused by
a surplus of animal protein and a
shortage of alkaline substances in the
diet exists for a long period of time. A
disturbance of the muscle pro t e i n
metabolism as well as the structure
and function of cartilage are other
negative consequences of the endoge-
nous compensation, which can also
aggravate degenerative diseases such
as arthrosis or rheumatism.
Our Stone Age ancestors preferred
a more or less mixed diet which in
spite of containing a high proportion of
animal protein was also characterized
by a surplus of base-forming sub-
stances. In contrast, the diet in today’s
Western industrial nations is charac-
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Fig. 16. Mean (± SEM) interstitial proton concentration during ingestion, exercise period
(solid line: citrate ingestion; dotted line: placebo) and recovery from exercise (n=7). *Sig-
nificant difference between citrate ingestion (CIT) and placebo (PLA). Modified from [38].
0.0 0.5 1.0 1.5 2.0 0 5 10 15 20 25
Übersichtsarbeiten ❘ Review Articles
terized by a large quantity of acid-
forming nutrients, above all due to the
surplus of animal protein. On the other
hand, a high proportion of fresh fruit
and vegetables in the diet contributes
to the formation of the surplus of bases
in the body.
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Address for correspondence:
Prof. Dr. rer. nat. Jürgen Vormann
Institut für Prävention und Ernährung
Adalperostrasse 37, DE-85737 Ismaning
vormann@ipev.de
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