Medical Hypotheses 73 (2009) 347356

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Acidbase balance and weight gain: Are there crucial links via protein
and organic acids in understanding obesity?
Shoma Berkemeyer *
Ruhr-Universitt-Bochum, Klinik fr Altersmedizin und Frhrehabilitation, Studienbro, Room 23, Widumerstr. 8, 44627 Herne, Germany

a r t i c l e

i n f o

Article history:
Received 9 September 2008
Accepted 12 September 2008

s u m m a r y
Obesity is associated with ever increasing social costs posing a general public health challenge. The most
obvious reason for obesity, given healthy body functioning, is a positive calorie balance. This article
delves into the lesser studied realm of the relationship of weight gain, in particular adipose tissue gain,
with increased hydrogen ion concentration, taking protein and organic acids as important caveats in this
discussion. The review opens the topic with the contradictory result of various studies reporting a positive relationship between chronic metabolic acidosis and weight loss. It goes to explain a process of
weight gain, primarily adipose tissue gain, on acidogenic diets. Insufficient dietary protein could lead
to muscle loss, and individual organic acids might indicate if there is any fatty acid oxidation or accumulation of hydrogen ion. The solution to the acid accumulation is discussed not in protein limitation but an
increase in the consumption of vegetables and fruits. Finally, this review article based on studies published puts forward a physiological basis including a hypothesis to explain the possible link between
hydrogen ion concentration and weight gain. This link could possibly explain the development of diseases
and aging partially, and warrants research.
! 2009 Elsevier Ltd. All rights reserved.

Introduction
Obesity is a known risk factor for diseases, such as, diabetes,
insulin resistance, cardiovascular diseases, and hypertension. The
number of people with obesity is increasing [1]. Obesity is also observed in childhood and adolescence [2,3]. Likewise, the number of
people with diseases such as, diabetes, insulin resistance, cardiovascular diseases, and hypertension are also increasing with earlier
disease onsets [46]. These trends have translated into increasing
public health concerns with greater efforts towards strategies for
their prevention.
The most obvious reason for weight gain, in the absence of diseases or malfunctions, is a positive energy balance. The Western
diet [7], a diet rich in calories, acid load, sodium salt, and glycemic
index but poor in fibers [810], is a foremost example of the modern
day dietary practice. Western diets health and disease consequences are currently under scientific investigation, primarily over
an unfavorable acidbase balance (ABB) [826]. This Western diet
is, however, not only characterized by high acid load but also calorie, so that, ABB and obesity could be related. This review focuses
and updates the current level of knowledge on the relationship of
ABB and weight gain or weight loss (WG or WL). It builds on the
caveats of protein consumption and organic acids on Western diets
to elucidate the relationship between ABB and WG or WL. Finally, it
* Tel.: +49 2323 4992622; fax: +49 2323 4992621.
E-mail address: shoma.berkemeyer@ruhr-uni-bochum.de
0306-9877/$ - see front matter ! 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2008.09.059

puts forward a hypothesis which might be a crucial link in understanding obesity warranting scientific investigation.
Section Weight gain or weight loss on chronic metabolic acidosis? of the review begins with the discussion on the reported WL on
chronic metabolic acidosis. Section Weight gain on acidogenic
diets updates on the association of acidogenic diets and WG. Protein and organic acids are important confounders in the understanding of ABB and WL or WG. Sections The protein conundrum
and The organic acid conundrum addresses to these issues. Finally,
section A culmination of acidosis and weight gain, given the caveats of protein and organic acids, from published literature brings
together the entire concept of WG and/or WL and ABB, via Western
diet, by putting forward a hypothesis as well. Studies are reported
that support the concept of WG via fat increase and the blood
hydrogen ion concentration or protons (H+). For this study, H+ has
been defined as a generalization to mean the total acid load, barring
section A culmination of acidosis and weight gain, given the caveats of protein and organic acids, from published literature and Table 1, where blood H+ is used to denote the blood free hydrogen ion
concentration.
Weight gain or weight loss on chronic metabolic acidosis?
Blood pH is highly regulated [27] and maintained within the narrow normal range of 7.367.44. Thus, when the blood pH dips below
the clinical normal, it would have been well preceded by various
body compensatory and adjustment processes, which ultimately

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S. Berkemeyer / Medical Hypotheses 73 (2009) 347356

Table 1
Synopsis of cellular studies on the relationship of obesity and cellular pH.
Author

Year

Journal

Disease

Conclusion

Positive association
Kaloyianni et al.

2001

Cell Phyiol Biochem

IR, Ob

NHE increases Na influx into cell by H+ efflux out of cell

Obese have lower cellular pH

Konstantinou-Tegou
et al.

2001

Mol Cell Endocrinol

Ob

Increase in adipose tissue perhaps linked to cardiovascular complications of Ob

Obese have lower cellular pH

Koren et al.
Aviv
Resnick

1997
1992
1992

Diabetologia
J Am Soc Nephrol
Am J Med

NIDDM
IR, HT, NIDDM
Ob, NIDDM,
HT

Increased cellular acidity might result in proteinuria

Increased NHE activity associated with increased free Ca in cells
Increased NHE activity associated with increased free Ca but lower Mg in cells

Resnick et al.

1991

Hypertension

Ob, NIDDM,
HT

Increased NHE activity not only increase cellular Na but also Ca, but lowers Mg
HT is associated with lower cellular pH

Negative association
Treuth et al.

2001

Ob

Family history of obesity does not change skeletal muscle energetics or cellular pH

Ghigo et al.

1994

Int J Obes Relat Metab

Disord
Eur J Clin Invest

Ob, DM2, HT

Increased NHE activity (increased cytosolic Na and higher alkaline pH) in HT but not DM2
or Ob

Abbreviations: IR, insulin resistance; HT, hypertension; Ob, obesity; NIDDM, non insulin dependent diabetes mellitus; DM2, diabetes mellitus type 2; H+, proton; NHE, sodium
hydrogen (H+) exchanger; Ca, calcium; Mg, magnesium, P(i)/PCr, intracellular phosphate to phosphocreatine ratio; pH(i), cellular pH.

could not avert the decline. That is to say, a blood pH change (opposed to fluctuations) is a long-term, slow change. A blood pH constantly at the lower end of the normal range has been termed latent
acidosis [28]. A blood pH constantly at or below 7.35 is clinically defined as chronic metabolic acidosis, which is known as a stress situation for the body [29].
Undernutrition, associated with WL, is characterized by accompanying metabolic acidosis. A classical example of undernutrition
is protein calorie malnutrition (PCM) per se or secondary to chronic
renal diseases (CRD) [2934]. It is known that starvation diets induce endogenous ketosis [35]. Patients of childhood epilepsy are
prescribed a ketogenic diet, which is known to slow weight gain
[36]. To generalize: undernutrition, e.g., PCM, CRD, starvation,
etc., is widely reported to be associated with acidosis, evenso this
result is not without contradiction. A review by Kalantar-Zadeh
et al. [32] elucidates the contradiction succinctly. Evidence from
metabolic studies suggest that metabolic acidosis is related to
WL through increased protein catabolism, which in turn is due to
increased activity of adenosine triphosphate (ATP)-dependent
ubiquitin-proteasome and ketoacid dehydrogenase. In contrast,
epidemiologic studies (on maintenance dialysis patients) suggest
that lower blood pH is associated with improved status of PCM.
In other words low blood pH is associated with WG. Finally, interventional studies yielded inconsistent results. To recapitulate,
there is the concept of WL on chronic metabolic acidosis, which
is not without contradiction as studies have also indicated WG,
or maintenance, on chronic metabolic acidosis. A statement of causality appears pertinent to the issue. Metabolic studies show
undernourishment leads to WL and metabolic acidosis due to catabolic stress [29]. The metabolic acidosis observed in affected population groups in epidemiological studies does not let infer
causality.
The concept of metabolic acidosis leading to low WG is perhaps
best documented in pediatric studies on preterm or low birth
weight term infants [17,3741]. This infant group requires greater
protein intake for catch-up growth, which is usually provided by
fortified human milk or formula milk. Studies have put forward
that the high protein intake of formula milk promotes the development of metabolic acidosis, which promotes WL instead of WG.
Hence, these studies suggest an alkali supplementation along with
formula milk to neutralize the excess H+ and promote growth.
Studies have also reported WG in infants on higher protein diets
[4244]. The protein supplement is thought to engender positive

protein balance through anabolic effects via growth hormone,

insulin-like growth factor I, carnitine and steroids [33]. These
above results introduce the protein conundrum, i.e., is protein
harmful or beneficial in terms of ABB, and this will be taken up
in the section Weight gain on acidogenic diets.
Like in the case of CRD, cases of low birth weight and preterm
infants are a group that are already affected by less than optimal
growth. Thus, therapy effects of protein diets in undernourished
people to achieve optimal growth and/or development with the
accompanying metabolic acidosis can be regarded in a slightly different light as excess protein and/or calorie consumption and a
metabolic acidosis thereof due to a diet of plenty. Finally, chronic
metabolic acidosis associated WL might be a characterization of
undernutrition, rather than the acidosis, since acidosis can be also
related to WG.

Weight gain on acidogenic diets

It is necessary to distinguish between the body endogenous
chronic metabolic acidosis and an acidogenic diet, since the two
terms are not synonymous [45]. An acidogenic diet is associated
with the increased probability to raise the bodys H+ load [7], if
the various compensatory and adjustment processes are exhausted. Chronic metabolic acidosis, however, is the condition,
when the development has gone as far, signaling a disequilibrium
in the ABB. It remains to be evaluated whether an increase in H+,
neither captured by a blood pH decline nor compensated via the
renal or the respiratory route, but, e.g., stored in cells instead, is
a welcome development in itself. Table 1 is a synopsis of cellular
studies showing the relationship of obesity to cellular pH along
with the convergence of ill-conditions of hypertension, diabetes,
and insulin resistance.
The first five studies in Table 1 shows that the concurrence of
obesity, hypertension, insulin resistance have been related to the
same underlying cellular basis, i.e., a generalized defect in cell
ion handling, specifically the sodium hydrogen exchangers (NHE).
NHE allows the exchange of intracellular proton with extracellular
sodium, with one study reporting hypertension to be associated
with lower cellular pH, i.e., less sodium influx into the cell [46].
A lower cytosolic pH has been observed by some study groups in
obese subjects [47,48] with a study reporting that it could lead
to protein loss in urine [49]. The latter study supports the concept

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S. Berkemeyer / Medical Hypotheses 73 (2009) 347356

of muscle loss in metabolic acidosis due to endogenous protein

catabolism [32]. Obese individuals had lower cytosolic free magnesium with higher free calcium compared to normal individuals
[46,50,51] supporting an ionic hypothesis in diseases development, explaining the concurrence of obesity, hypertension, and
insulin resistance. An ionic base is central to ABB [14,22,45]. Thus,
this ionic base could be a common pathway linking ABB with the
development of obesity, hypertension, insulin resistance, partially
explaining the development of diseases on consumption of acidogenic diets due to a longer term disequilibrium H+, indirectly, the
anions and cations.
Epidemiological studies on the relationship of H+ and WG are
few. Three studies on patients with renal stones reported an inverse relationship between measures of WG (BMI or weight) and
the urine pH [5254] (Table 4), so that as H+ is higher there should
be greater weight (WG). An experimental study on otherwise
healthy but obese subjects [55] reported that on a protein-free diet,
obese individuals excreted more H+ in the urine than could be accounted for by oxidation of sulfur to sulfate. Sulfur from protein is
a chief contributor to the bodys acid load [45]. In other words,
there is a loss of endogenous protein, i.e., muscle mass, even so
the subjects are obese on protein deficient diets. That is, in total
there is WG (obesity), even so there is WL as far as muscle mass
(endogenous protein loss) is concerned. This corroborates the reported WL on undernutrition [32].
Another clinical study reported the acidbase responses to a
hypoenergetic protein and a hypoenergetic glucose diet, in obese
individuals [56]. The protein diet resulted in mild acidosis, greater
excretion of urinary ammonium and urea nitrogen, and ketosis but
with better nitrogen balance compared to the glucose diet. A subsequent fast resulted in greater acidosis in the glucose meal group
than in the protein group. This suggests, long-term consumption of
calorie reduced, protein-poor diets would possibly result in poor
nitrogen balance (nitrogen and weight loss to that extent) with
development of acidosis, even so in total obese.
Clinical studies have reported a greater loss of magnesium on
acidogenic diets [55,57] and a fall in blood pH in response to acidogenic diets [58]. Observational studies on community dwelling
healthy young adults and healthy elderly corroborate the loss of
magnesium with higher dietary acid loads [59] and that urine pH
is inversely associated with BMI (WG) and directly with muscle
mass [60].
To generalize, cellular studies report obese people had lower
cellular pH compared to normal weight (Table 1). Results reported
by Frassetto et al. [58] let infer a somewhat causal role of Western
diet in the blood pH decline in healthy people. The remaining body
of studies indicate that the Western diets are associated with lower
pH and obesity. It is hence appropriate to reconsider the core biochemicalphysiological dynamics of this relationship.
Undernutrition implies emaciation and general tissue loss, muscles and fat, to provide endogenous sources of energy. In undernutrition the muscle loss would also partly supply ammonia, to buffer
and excrete the acid load [58], a sizable amount being also the organic ketoacids. The body would use fat stores and have a higher
rate of beta oxidation. These processes would lead to general tissue
loss (WL), with accompanying metabolic acidosis as reported in the
section Weight gain or weight loss on chronic metabolic acidosis?.
Acidogenic diet is a dietary pattern subsequent to civilization
process, i.e., a change from hunters and food-gatherers to agriculturalists to industrialization, and post-industrialization [7].
Thus, Western diet is a dietary concept of nutrition in plenty.
The combination of high acid and high energy consumption on
Western diet supports development of acidosis with time (age)
and down-regulation of fatty acid oxidation since the diet is energy rich (glucose preferred energy substrate). A certain amount
of muscle protein loss, as endogenous ammonia buffer, could

Western diet

Acidosis
(latent &/ metabolic)
(volatile &/ fixed acid

Ill-conditions
Diseases
Aging

Fig. 1. The straight line hypothesis of diet, acidosis, and aging.

accompany the process to neutralize the acid load, acerbated on

protein deficient diet. It could be for such reasons that Jourdan
et al. [55] reported that obese people on protein-free diets excreted greater amounts of H+ as could be accounted by dietary intake of sulfur (protein) [55]. That is, if there is insufficient dietary
protein intake there will be muscle loss, irrespective of whether
the person is obese or underweight, hence a poor nitrogen balance [56]. If diet is additionally characterized by high energy
intake, as in Western diets, it implies only a concomitant accumulation of fat mass (WG), at a loss of endogenous muscle protein
(WL). In fact, the ratio of fat to muscle mass might increase over
time. So, a relatively healthy person on Western diet would run
the risk of losing muscle relative to fatty tissue; possibly becoming relatively obese in the longer run, which would be acerbated
on a low to no protein diet. If a sub-clinical latent metabolic acidosis would set in, the dietary life-style dependent acidosis itself
would further support the latent acidosis, since before a complete
recovery or adjustment can occur the next food intake would take
place. In the longer run, this could lead to a metabolic acidosis but
a metabolic acidosis of plenty (Fig. 1), which would be different
from the metabolic acidosis of undernutrition. Both routes to acidosis implies body stress, and hence a certain amount of stress related catabolic processes [29,32], i.e., muscle breakdown. The over
or malnutrition related acidosis, when unchecked, can be visible
as disease complications (hypertension, diabetes, cardiovascular
diseases) with time (age), which has been termed as the cascade
effect [22].

The protein conundrum

A discussion of the dietary protein emerges somewhat central
to the understanding of the concept of WG or WL in relation to acid
load. It is well-known that the dietary proteins are one the chief
sources of the dietary acid load [45], especially in the form of
methionine and cysteine. Methionine and cysteine are some of
the few amino acids containing sulfur, the sulfur contributing to
the dietary nonvolatile, fixed acid load [45]. This has been a reason
to recommend animal protein limited diets [16], in order to control
the dietary source of acids [26]. The strong sulfuric acid, when in
excess of body requirements, requires to be excreted, one of the
many reasons why CRD patients are also recommended protein
limited diets.
A protein duality in acidbase studies has been reported [61].
Protein increases the total acid load but also allows the kidneys
to increase their net acid excretion capacity (NAEC), so that the
body can excrete the excess H+. This is a normal body compensatory process. Cysteine (a hydrophobic amino acid with a sulfhydryl
group) is found in most protein sources but in very small quantities. Usually, therefore, it requires to be synthesized in the liver
from methionine, an essential amino acid. Rich sources of methionine are meats, fishes, cottage cheese, to name the important. The
very cysteine that contributes to the non-volatile acid load is also
the rate-limiting step in the production of glutathione, the most
common intracellular antioxidant, protecting cells from oxidative
stress and cell death [6264]. Animal studies show that an ade-

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S. Berkemeyer / Medical Hypotheses 73 (2009) 347356

quacy of the dietary sulfur amino acids determines the extent to

which antioxidant defenses are maintained during inflammation
[65]. This could exactly be a means to maintain a healthy aging
process, since aging is associated with net altered gene expression
leading possibly to a net higher production of reactive oxygen species (ROS) with time [66,67]. In fact, gerontology studies prescribe
a consumption of adequate amounts of dietary protein from high
quality sources as an important means to slow down or treat sarcopenia [68]. Interestingly, elderly compared to younger subjects
had a depressed response to stimulation of muscle protein synthesis following administration of mixed meals due to a decreased
ability to respond to anabolic stimuli, such as insulin. Likewise,
the anabolic effect of amino acids seems blunted on low protein
doses [69]. To summate, proteins are the building blocks of the
body and while ad lib over-consumption, as with all excesses,
would have deleterious consequences, it still does not gainsay an
adequate requirement of it at all ages.
Taking another example of wasting in HIV/AIDs, which is characterized by loss of cysteine, methionine, and carnitine, it is known
that the carnitine is synthesized from cysteine and lysine. Carnitine
is normally found in high levels in muscles and is responsible for
the transport of long-chain fatty acids into mitochondria for beta
oxidation. Thus, a dearth of cysteine or in general high quality
proteins could mean a reduction in the amount of glutathione antioxidant, and possible accumulation of adipose tissue, which a low
to no protein intake, quantity and quality, would only acerbate.
Regulated protein consumption, including high quality red meats,
would help maintain carnitine and glutathione levels. A third
example would be in maintenance of the bone-protein-collagenmatrix [70,71]; even so excessive consumption of the non-neutralized dietary proteins could result in bone calcium leaching
[11,12,19,23,24,72]. The lack of adequate concomitant consumption of alkalis (vegetables and fruits, base supplements), rather
than the protein, is probably responsible for the leaching [73],
which is characteristic of Western diet [7,26,58,74]. This reduction
in alkali consumption is possibly what needs rectification [19]
rather than decreasing protein consumption.

Western diet

The organic acid conundrum

It has been recently shown that healthy people had a more-orless constant total organic acid excretion on mixed diets once body
surface area was factored out [75]. The reasons for such an observation are not very well understood. Organic acid excretion is partially diet-dependent, as already successfully demonstrated [45].
Thus, the formula for endogenous total organic acid production
[45] (Eq. (1)), often extrapolated for organic acid excretion, shows
it to be a function of dietary intakes of acids (excluding sulfur),
termed as the dietary unmeasured anion:

OAdiet 32:9 0:15 $ Dietary unmeasured anions

where,

Dietary unmeasured anions Na K Ca2 Mg2

&

& Cl 1:8PO4

Empirically it is well-proven that with higher dietary ingestion

of acids there is higher urinary excretion of it as well, i.e., the net
acid excretion (NAE) is higher. NAE is directly measured in urine
by summing up titratable acidity and ammonium, and subtracting
the bicarbonate. A measurement of total organic acids excretion in
healthy people commenced principally because, apart from sulfur
and phosphates, it was identified as the third most important component of the bodys NAE [45]. Thus, with higher dietary intakes of
acids, the NAE is also higher. It is possibly for such reasons that it is
understood that the excretion of sulfur, phosphates, and total organic acids is also higher. This is supported by the fact that the dietary intake dependent excretion of each of these components
cannot be disregarded. But while this might hold good for sulfur
and phosphates, there is reason to believe that this is physiologically not completely the case for organic acids, as supported by
the empirical finding of a largely constant total organic acid excretion in health, having accounted for body size [75].
The body endogenous production of organic acids, either due to
metabolism of dietary intakes and/or endogenous metabolic processes, is rather difficult to estimate due to the ready conversion

Lactic acid increases,

most of lactate converted
into CO 2, some to fat and
glycogen

Respiratory alkalosis

Cell lactic acid produced

Mild proton retention

CO2 increases, hypercapnia

Mild cellular
acidity at normal
blood pH

Respiratory acidosis

Activation of hypoxic /
hypercapnic
chemoreflex
Mild inhibition of
mitochondrial energy
production

Hyperventilation,
(Obesity increased
hyperventilation)

Some pyruvate
accumulation
O2 increases
Fig. 2. The lactic acid trap.

Next Western meal

ingestion

Cell pH decrease a bit more

than the ph of the last cycle

Only regular consumption of

vegetables and fruits or alkali
dosage to get out of trap

S. Berkemeyer / Medical Hypotheses 73 (2009) 347356

of organic acids into carbon-dioxide and water and vice-versa. Organic acids, which are volatile acids, remain in a constant state of
flux in the body endogenous condition. Traditionally, individual organic acids are measured in urine in order to diagnose certain disease conditions, such as the inborn errors of metabolism, or
poisonings. The constant state of flux of endogenous organic acid
production renders the estimation of it with pitfalls. Yet in spite
the OAdiet is rather a reasonable estimate of total organic acid production (extrapolated for excretion) on net acid diets [75]. However, on net alkaline diets, OAdiet (Eq. (1)) predicts a negative
organic acid production, which might be physiologically not
tenable.
The organic keto acids
The keto acids are one the major endogenous organic acids. In
the 1980s there was a row of experiments conducted by Chalmers
et al. [76] which went to show that in relatively healthy subjects
the total organic acid excretion hardly varies. Another independent
study reported that the production of keto acids increases in subjects who ingested alkalis, specifically, sodium bicarbonate [77].
This implies if the body has a greater intake of dietary net alkalis,
the body produces more organic keto acids of purely endogenous
origin. Thus, a relative constancy in organic acid excretion having
accounted for body size is possible even on net alkaline diets
[75]. The study by Hood et al. [77] reported that in conditions of

351

moderate acid load there was a reduction in organic keto acid production of endogenous origin. Thus, with acid ingestion it seems
that the body down-regulates endogenous production of organic
keto acids and would in preference excrete the exogenous, dietary
organic acids, thereby maintaining a relatively constant net organic
acid excretion, once corrected for body surface area. To that extent
OAdiet would then exaggerate the dietary alkalinity when calculating the net endogenous acid production [45], on net alkaline diets.
The other available formula (Eq. (2)) for total organic acids is
based on anthropometry (OAanthro) [75] and it estimates the total
organic acid excretion. In the process it avoids the pitfalls of estimating the endogenous production of organic acids, in that, it
never estimates it, but thereby provides a means to show that
the total organic acid excretion is largely a constant, having accounted body surface area:

OAanthro body surface area $ 41=1:73

where, 41 is the median daily organic acid anions excretion (mEq/d)

at an average body surface area of 1.73 m2 for healthy subjects.
The increase in endogenous keto acid production on alkaline
diets [77] so that the total organic acids remain largely a constant
[75] indicates a step-up in fatty acid oxidation on alkaline diets via
beta-oxidation. This could go some way to explain the weight
maintenance to WL on net alkaline diets; often higher vegetables
and fruits consumption compared to net acid diets, e.g., Western
diets. This suggests why possibly Western diets in the longer run

Table 2
A synopsis of relationship of hydrogen ion with weight gain in obese in comparison to normal controls.
Author

Year

Journal

Treatment

Conclusion

Epidemiological
Harper et al.

2002

Diabetes

Six weeks of 900 kcal meal

Proton leak correlate with weight loss success

Clinical
Gougeon et al.

1992

Am J Clin Nutr

Two very low calorie diet, with isocaloric

high and low quality proteins

Perhaps insufficient exogenous protein intake results in loss of muscle

tissue in obese

Gougeon-Reyburn et al.

1991

Am J Med Sci

Neutral to alkali intervention in

ketoacidosis (induced by very low energy
protein diets)

Excretion of magnesium associated with acidosis

Urinary acid load decrease with alkali supplementation

Gougeon-Reyburn et al.

1989

Am J Clin Nutr

Two hypoenergetic diets, one protein other

glucose
Second intervention: a fast following the
above diets

Dietary protein is net acid producing but also prevents the body from
going into negative nitrogen balance

Hood et al.

1988

Metabolism

Methionine, like ammonium chloride, results less endogenous ketoacid

excretion

Jakober et al.

1983

Hood et al.

1982

J Endocrinol
Invest
Am J Physiol

Intervention (methionine, ammonium

chloride, and sodium chloride) in
hypocaloric ketogenic fast
Exercise after prolonged starvation

Jourdan et al.

1980

Sonka et al.

Sodium bicarbonate and ammonium

chloride intervention after fasting

Prolonged starvation changes basal values of metabolites and hormones

but not their exercise induced shifts compared to normal
With increase in acid production less endogenous ketoacids are excreted
so that systemic acidbase status can exert feedback controls

Am J Clin Nutr

Metabolic unit for 63 days with differing

protein and calorie liquid formula diets

Increased loss of calcium and magnesium on acidogenic diets

Perhaps, both, protein intake and protein free diets increase acid excretion

1978

Endokrinolgoie

Administration of sodium bicarbonate

Fasting led to lipoylsis even in obese

The acidosis due to fasting can be corrected with intake of alkalies

Bray et al.

1977

Metabolism

Varying levels of exercise

Maybe overweight leads to hyperventilation

Overweight people seem to run the risk of developing insulin resistance
with higher blood pressures
Lack of enough growth hormone in overweight which could lead to lower
level of growth hormone functions

Goeschke et al.

1976

Res Exp Med

(Berl)

Four to six days of fasting

Lean women probably require higher alkali intake than their men
counterpart when fasting

Sapir et al.

1975

Metabolism

Total starvation

Possibly a constant organic acid excretion

Conservation of ketone bodies minimizes body protein loss, and prevents
large urinary losses of cations during prolonged starvation since
ammonium becomes the major cation excreted

Sapir et al.

1972

J Clin Invest

Consumption of minute quantities of

carbohydrate during prolonged starvation

Carbohydrate ingestion in starvation has nitrogen sparing effects by

reducing urinary ammonium excretion
The urinary ammonium excretion is possibly an indicator of tissue loss

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S. Berkemeyer / Medical Hypotheses 73 (2009) 347356

could indirectly promote WG. A direct promotion of WG would be

simply due to the high energy intakes on Western diet as discussed
in the section Weight gain on acidogenic diets. Section Weight
gain on acidogenic diets also reported the study by Jourdan et al.
[55] which shows that inspite of obesity (WG) there was concomitant muscle loss (endogenous protein loss). This was explained as
relative obesity on Western diet in the section The protein
conundrum. The dynamics of this relative obesity could be further
linked to the hitherto not discussed organic lactic acid, and its production on Western diets.
The organic lactic acids
Lactic acid is another important endogenous organic acid. An
animal study reported that kidney and liver mitochondria, isolated
from acidotic murine models had lower mitochondrial energy production (MEP), than controls [78]. A human study reported an inhibition of the MEP in methylmalonic aciduria [79]. These studies
support a decline in MEP due to acidosis, hinting at inhibition of
the tricarboxy acid cycle (TCA), though not glycolysis. This implies

a collection of the organic pyruvic acid (pyruvate); normally referred to as incomplete carbohydrate metabolism. Pyruvate accumulation would lead to increased levels of the organic lactic acid
(lactate), not associated with physical exercise. All tissues can produce lactate under anaerobic conditions (hypoxia) but tissues with
active glycolysis, e.g., muscles, brain, skin, red cells, gut, produce
excess lactate due to the interchangeability of pyruvate and lactate,
i.e., lactic acid production even in the presence of oxygen. Prolonged consumption of the Western diet could lead to a certain degree of lactacidosis, not measurable in renal NAE, which could
inhibit MEP. Lactic acid being a volatile organic acid can be exhaled
via respiratory compensation. However, if there is hyperventilation, e.g., in stress situations, then the body would continue to be
exposed to organic lactic acid with no recovery.
Hyperventilation leads to respiratory alkalosis. The stickiness of
haemoglobin for oxygen increases, resulting in less oxygen being
released into cells. To counteract the alkalosis, cells begin to produce lactic acid, which lead to tiring and aching muscles. In our
example, there was already a high lactic acid production, from glycolysis which never entered the TCA cycle. This could be compen-

Table 3
A synopsis of relationship of hydrogen ion with weight gain in normal, disease free people.
Author

Year

Journal

Treatment

Conclusion

Prospective
Yancy et al.

2007

Eur J Clin Nutr

Low-carbohydrate ketogenic diet

Low-fat diet

Healthy people on ketogenic/low fat diet do not show

significant metabolic derangements

Clinical
Roef et al.

2003

Four hours cycle exercise, then either sodium lactate or sodium

bicarbonate infusion

Gluconeogeneis can be used to sustain blood glucose

after overnight fast if lactate available

Miyamura et al.

1998

Am J Physiol
Endocrinol
Metab
Jpn J Phyiol

Exercise till exhaustion

Within normal weight, weight increase is associated

with low levels of dopamine

Lin et al.

1997

Am J Physiol

Four received sodium chloride infusion (acid)

Acid ingestion in fasting leads largely to potassium

conservation
Base ingestion in fasting leads to potassium excretion

Brengger et al.

1997

Am J Physiol

Ammonium chloride intervention

Vittone et al.

1997

Metabolism

Growth hormone releasing hormone (GHRH) as nightly doses

Rankin et al.

1996

Kundu et al.

1991

Med Sci Sport

Exerc
Clin Chem

Hypoenergetic diets followed by either high or moderate

carbohydrate diets
Subjects on restricted calorie weight loss programs

Mitchell et al.

1990

Am J Med Sci

Exercise to exhaustion performed under intervention of no infusion

(control), sodium bicarbonate and sodium chloride

Greenhaff et al.

1988

Dominguez et al.

1976

Eur J Appl
Physiol Occup
Phyisol
J Clin
Endocinol
Metab

Two exercise episodes after two 4-day isoenergetic diet intervention

of low carbohydrate, high fat and protein or high carbohydrate, low
fat and protein diets
Dietary phosphate restriction

Sutton et al.

1976

Clin Sci Mol

Med

Ergometer exercise at 33%, 66% and 90% of VO2 max with ammonium
chloride, sodium bicarbonate, and calcium carbonate intervention

Possibly lactacidosis is compensated via respiratory

route in health
Metabolic acidosis is less associated with anaerobic
lactic acid production
Beneficial effects of exercise and alkali intake possibly
via increases in GH

Stinbaugh et al.

1975

Metabolism

Systemic alkalization with either sodium lactate or sodium

bicarbonate

Alkalization of system in fasting induced ketosis

results in no change in net acid excretion, even so the
total number of free protons excreted increases

Observational
Remer et al.

2007

Eur J Clin Nutr

As body fat is higher urinary pH is lower

As body muscle mass is higher urinary pH is also
higher

Rouslin

1983

J Biol Chem

The proton load can inhibit mitochondrial energy

production

Five received sodium bicarbonate infusion (alkali)

Metabolic acidosis might decrease thyroid hormones

and their functions
Optimizing GHRH might attenuate some effects of
aging on skeletal muscles
High carbohydrate group recovered performance and
moderate did not after exercise in health
Fat loss better determined by blood or breath ketone
bodies production and not urinary ketonic (organic)
acids excretion
In health, alkalization possibly improves exercise
endurance with less glucose exhaustion and greater
anaerobic respiration
Blood pH is tightly regulated

Dietary phosphate deficiency (associated with dietary

protein intake) can lead to hypercalciuria and
negative calcium balance in women but not men

S. Berkemeyer / Medical Hypotheses 73 (2009) 347356

sated via respiratory route. If, however, there is hyperventilation, it

would result in lactic acid to be expired out temporarily, only to be
produced again in the cells, in response to the hyperventilation.
Thus, lactacidosis would continue, within the range of what is
broadly classified healthy (no clinical symptoms), still not measurable as the renal NAE, latter which, would have a relatively constant organic acid excretion. If there is no or reduced respiratory
compensation, the next Western meal intake will only acerbate
the problem, possibly setting in a lactic acid trap, given no change
in dietary habits (Fig. 2). Apart from inefficient MEP and beta-oxidation, the inhibition of the TCA cycle due to acidosis, e.g., lactacidosis, would make electrons available for the production of ROS
instead [67]; certain amount of lactate could also be converted into
fat. Hence, a possibility of developing degenerative diseases in the
longer run, perhaps even a contribution to aging process cannot be
ruled out, as put forward in the straight line hypothesis of diet, acidosis, and aging (Fig. 1).
A culmination of acidosis and weight gain, given the caveats of
protein and organic acids, from published literature
Tables 24 list studies examining the relationship of the blood H+
concentration in obese (Table 2), in normal weight, disease free (Table 3), and in some patient-groups (Table 4), respectively. The success of WL in obese has been related to those who tend to respond
to dietary intervention and those who do not; the diet responsive
group reported to be successful in WL principally via the mechanism of proton leak [80]. Animal studies indicate that proton leak
accounts for 2025% of the resting metabolic rate (RMR) [81,82].
Muscle energy expenditure accounts for 20% of standard metabolic
rate, and proton leak is observed in muscle tissue and explains 20
25% of muscle tissues RMR; hence indirectly proton leak accounts
about 5% of the standard metabolic rate between diet responsive
and non-responsive group [80]. Harper and colleagues have further
proposed that only thyroid hormones seem to regulate the proton
leak [83,84]. Metabolic acidosis itself has been reported to decrease

353

thyroid hormones and hence their functions (nitrogen balance, protein synthesis, lean body mass, insulin-like growth factor I, cardiac
contraction, and renal acidification) [13]. Thus, a higher H+ could inhibit thyroid hormone function [13]. Thyroid hormone is also reported to regulate proton leak and indirectly heat production
[83,84] leading to lower resting metabolic rates, resulting in a obesity not responsive to dietary interventions [80].
A study on 12 animal species, including humans, reported that
H+ itself can inhibit mitochondrial energy production (MEP) [85]
(sections Weight gain on acidogenic diets and The organic acid
conundrum) explained via inhibition of TCA [78] and accumulation of lactic acid on Western diets. The latent acidosis on Western
diets could lead to lactacidosis when not efficiently or effectively
compensated via the respiratory route could imply a prolonged
exposure to acidosis (latent or metabolic). The inhibition of the
MEP due to acidosis could divert the electrons in the production
of ROS [67], possibly explaining disease development and aging
with time (age), as put forward in the straight-line hypothesis
(Fig. 1). This hypothesis is corroborated with the observation of
elevated ROS and cytokines in diabetics [86]. This lactate production cannot be confused with anaerobic lactate production which
is a normal body response to exercise [87,88], which, in health is
compensated by the respiratory route [89]. Section The organic
acid conundrum reviewed the H+ due to lactacidosis. This acidosis
could inhibit thyroid functioning and the proton leak making the
symptom of low heat production and lower MEP occur simultaneously (Fig. 3). The lower energy required for maintaining RMR
would partly adjust the lower MEP; i.e., the body would down-regulate its energy requirement as adjustment.
More importantly, overweight (WG) has been reported to lead
to hyperventilation [90]. This supports the straight-line hypothesis
(Fig. 1); that both calories and acids can be accumulated on Western diets, which could produce lactacidosis with concomitant less
endogenous ketoacid production, thus accumulate adipose tissue
with lower fatty acid oxidation (Fig. 3). Thus, there would be a tendency to become overweight with time (Figs. 1 and 3). The over-

Table 4
A synopsis of relationship of hydrogen ion with weight gain in various disease groups.
Author

Year

Epidemiological
Taylor et al.
2006
Siener et al.
2005
Maalouf
2004
et al.
Clinical
Tuma et al.

2005

Journal

Disease/treatment

Conclusion

Am J Kidney dis
J Urol
Kidney Int

Renal stones
Renal stones
Renal stones

Urinary pH inversely related to weight gain

Urinary pH inversely related to weight gain
Urinary pH inversely related to weight gain

Diabetes mellitus II

Obesity and diabetes mellitus II are associated with loss of skeletal muscle

Treatment for acute respiratory failure for 6

8 months
Diabetic ketoacidosis (DKA), with and
without obesity with controls

Possibly the development of respiratory acidosis in patients with acute

respiratory failure
DKA associated with elevated proinflammatory cytokines, reactive oxygen
species and cardiovascular factors in absence of obvious infection or
cardiovascular pathology
Neutralized protein intake, i.e., correction of acidosis, is beneficial for protein
turnover

BaHammam
et al.
Stentz et al.

2005

J Chromatogr B:
Anal Technol
Biomed Life Sci
Respir Med

2004

Diabetes

Graham
et al.

1997

Kidney Int

Kopple et al.

1995

Kidney Int

Reaich et al.

1995

Am J Physiol

CRF/Leucine infusion, before and after

correction of acidosis with bicarbonate

Reaich et al.

1993

Am J Physiol

CRF/First: Leucine intervention

Second: Sodium bicarbonate intervention
Third: Sodium chloride intervention

The more acid neutralized protein supplement resulted in less endogenous

protein loss, lower exogenous protein required for tissue building/
maintenance with least amount of protein used for energy production, hence
lower catabolic rates

Nery et al.

1983

Chest

Chronic obstructive pulmonary disease

(COPD) and mitral valve disease/exercise
intervention

Compromised oxygen delivery to muscles in mitral valve disease

COPD group unable to increase ventilatory gas exchange sufficiently to match
the exercise induced carbon-dioxide production

Chronic renal failure (CRF)/Leucine infusion,

before and after correction of acidosis with
bicarbonate
CRF/Dialysate substituted with amino acids

Amino acid intervention might improve protein malnutrition in chronic renal

disease patients ingesting low protein intakes
Acidosis contributes to the insulin resistance in chronic renal failure but does
not affect the action of insulin on protein degradation

354

S. Berkemeyer / Medical Hypotheses 73 (2009) 347356

Metabolic / latent acidosis

Less thyroid hormone

(IGF-I, GH)

Less
IGF-I

High calorie
intake from
Western diet

Less proton
leak
Reduced
thermogenesis

Lower
anabolic
processes

If obese, not
responsive to
diet therapy

Decreased
heart
contraction,
decreased
renal
acidifying
property

Lower
nitrogen
balance and
protein
synthesis

Cardiovascular
disease

Muscle protein
breakdown, if
no/less protein
intake

Inhibition of
mitochondrial
energy
production

Lactacidosis
hyperventilation

Electrons
converted
to ROS

Lower endogenous
ketoacid production
net fat deposition
OBESITY

Lactic acid
trap /
Acidosis
worsens

Aging

Fig. 3. Possible pathology of diet-dependent latent or metabolic acidosis.

weight in itself could also support the hyperventilation [90], which

with no change in dietary habits would lead to a repetitive cycle of
mild lactacidosis, perhaps a lactic acid trap (Fig. 2), initially not visible as diseases, but with (age) (Figs. 1 and 3). This is supported by,
that overweight (WG) is associated with diabetes mellitus II, insulin resistance and/or higher blood pressures, and chronic renal failure [9092], skeletal muscle loss [92] lower growth hormone
functions [90], low dopamine [93], and increase in proton excretion [20,53,54,60].
It becomes important to state that this overweight (WG) would
be principally due to an increase in adipose tissue. The above processes elucidate that there would be less fatty acid breakdown and
a tendency of greater fat synthesis, indirectly due to acidosis, directly due to the calories (sections The protein conundrum and
The organic acid conundrum). Thus, WG requires differentiating
the WG into fat mass gain or muscle mass gain. Loss of non-dietary
nitrogen has been associated to increases in the H+ load [94,95]. A
protein deficient diet would intensify the loss of muscle protein on
acidogenic diets (section The protein conundrum). This suggest
that what is required is not a protein-deficient diet but a balanced
diet providing both high quality proteins with high intake of alkalies (vegetables and fruits, base supplements) so that the acid anions of the protein intake get neutralized [19]. There are studies
that mention the benefit of acid load neutralized diets [96,97]
which was associated with lower skeletal mass catabolism and improved protein turnover. Thus, Western diets could lead to the
development of selectively deficient nutrition; e.g., deficient vegetables and fruits intakes, with or without protein intake deficiency,
but also in micronutrients, vitamins, and minerals, even so there is
concomitant energy overnutrition, leading to loss of muscle mass
but adding to the adipose tissue (relative obesity). This with no
change in dietary habits, in the long run (age), can promote overweight to obesity, with or without diseases.
Conclusion
This review suggests:
' Undernutrition is characterized by general emaciation, whereas
overnutrition, such as on Western diets, is characterized with
relative obesity, leading to long-term increase in fat mass but
less of muscle mass.

' Both under and overnutrition are conditions of catabolic stress

for the body and related to the risk of developing H+ retention.
' The loss of muscle mass is acerbated on a protein deficient diet,
even so protein adds to the acid load of the body.
' The correction of acidosis warrants urgent increased consumption of vegetables and fruits and/or alkali supplements. A regular
consumption of these would prevent the acidosis from setting
in, in the first place and should be vigorously targeted as a
health objective.
' Concomitant to food practices, breathing dynamics are just as
important, i.e., not only diet but also breathing is important in
ABB. Ignoring any of the two, diet or breathing, could lead to disease complications and/or aging through concomitant net
increases in adipose tissue and ROS.
The review puts forward that what we eat and how we
breathe are two important cornerstones in ABB maintenance,
which might affect general health, disease etiology, and aging as
put forward in the straight-line hypothesis. Support for the
straight-line hypothesis can be partially drawn from published literature though urgently warranting targeted studies in this
direction.
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