General concepts of neutrality regulation

General

Concepts

of Neutrality

H. N. CHRISTENSEN,

M.D.,

From tbe Department of Biological Chemistry, The University of Michigan, Ann Arbor, Michigan.

T

origins of metaboIic strains to the neutraIity have not aIways been cIearIy perceived. The medica world has been beset by a curious mode of explaining how the neutraIity is deranged and then corrected, using baIances of minera ions, such as, Na* and CI-. This approach hardIy aIIows that an acidosis can deveIop without reference to the intake and output of such ions, although the fasting patient unquestionabIy wiI1 become acidotic if he is totaIIy without urinary function and other routes of gain or 10~s. A system of exposition that faiIs to account for endogenous strains on the neutrality or pIaces them in an obscure category cannot be serving us weI1. Let us see whether or not we can more successfuIIy account for the recognized metaboIic inffuences on neutrality by Iooking for the production and consumption of hydrogen ion rather than for gains and losses of fixed ions. To do so is, in a Iarge degree, to return to the concepts of the Van SIyke-Hastings schoo1 and the cIassic biochemical teaching, aIthough avoiding terms whose meanings have subtIy changed so as to confound us. The view has often been heId that intermediary metaboIism produces such unIimited quantities of hydrogen ions that a secure comprehension of neutraIity contro1 can scarceIy be buiIt on the study of hydrogen-ion production. This view overIooks the very cIose balance ordinariIy existing between hydrogen-ion production and hydrogen-ion destruction. If such a neutral substance as gIucose is cataboIized to such an anion as Iactate, one H+ must as a chemica1 necessity be reIeased for each Iactate ion formed :

Regulation

Ann Arbor, Michigan

Hf must again disappear: Lactate-

+ H+ 2 carbon dioxide and water

(2)

HE

GIucose -+ z Iactate-

+ 2H+

(1)

But as cataboIism proceeds, the Iactate is again converted to neutra1 substances and the American

Journal

J Surgery,

Volume

103,

March

1962

286

SimiIar sequences may be written for fatty acid oxidation and for the catabolism of most of the amino acids, urea appearing as an additiona1 neutra1 product. We may take it as a genera1 principIe, if a neutra1 dietary component yieIds neutra1 excretory products, onIy transient reIease and no net production nor consumption of hydrogen ion can occur. By extension, if a substance taken in with a given state of charge is excreted as products with the same net charge, presumabIy no net effect on the hydrogen-ion baIance can arise. In a number of instances, however, the stage producing hydrogen ion is isoIated from the stage destroying hydrogen ion or vice versa. For exampIe, our food may contain substantia1 quantities of such metaboIizabIe anions as citrate or Iactate. In this case we isoIate the Iast stage (2) of the sequence; as the Iactate ion is changed to the neutraI products, CO2 and water, then equivaIent amounts of H+ wiIl disappear. The ingestion of Iactic or citric acid, in contrast, if not exceeding amounts that can be fuIIy cataboIized, wiI1 have no Iasting action on the neutraIity. As a contrasting exampIe, the cataboIism of the suIfur-containing amino acids yieIds the suIfate ion, which cannot be excreted as an uncharged substance (aIthough its esterification is a step in this direction) : Methionine

2 urea, carbon dioxide, water + SO4- + 2H+

(3)

Our food must inescapabIy contain such amino acid suIfur; hence our neutraIity tends aIways to be under this strain. Furthermore it is a variabIe Ioad. In ketosis the hydrogen-ion producing stages of fat catabolism run ahead of the hydrogen-ion

General consuming

Concepts

of NeutraIity

the metabohcally bloodstream :

stages:

34 PaImitate- 2

2

acety1 coenzyme A + zH’

acetoaLLte_ 2

COz + 1~204

+ H+

carbon dioxide and water

+

C02(NHJsCO

+ 2H+ + H,O

K’COO-

HzC03 H+ + HCO,- 3

through

Hz0 + CO?

the

(7)

CO2 is all excreted neutral, gaseous form, its acidifying effect is entirely transient. If the first stage, CO2 production, goes ahead or falls behind the latter stage, CO2 excretion, we have the respiratory disturbances of neutrality, which lie outside the scope of this presentation. When HC03- is administered we tend to obtain the H+-removing stage without the H+-forming stage, Ieading to an alkahnizing action. When HC03- is excreted into the urine, the final stage of sequence (7) is prevented and hydrogen ions are left deserted in the organism; hence, any existing aIkaIotic trend is opposed by HCOIexcretion. SimiIarIy, the Ioss of bicarbonate by way of Iost gastrointestinal secretions wil1 also Ieave the deserted H+. I am incbned to generalize from the foregoing and to assert that acidifying action cannot be ascribed to any physiologic event unless a reaction can be written to show that the event yields hydrogen ions. For a few events commonly taken to be acidifying but for which such a reaction is not apparent, my response is to question whether or not these reaIIy are acidifying events. The catabolism of most phosphate monoesters does not include net H+production, contrary to the assumption of the writers of some oIder textbooks. The renal retention per se of phosphate or sulfate, as far as I can understand, cannot tend to acidify the organism, except to the extent that the increasing of the extraceIIuIar fluid voiume bv- an,y solution not containing HCOZ- or its equivalent tends to be acidifying. In such cases new EtCOamust be generated to buffer the added portion of extraceIIuIar fluid at the proper pH. Generating this extra HCOs- wiI1 of course lead to H+ production:

(5)

?,5 urea + H+ carbon dioxide + water; + H’ 2 carbon dioxide + water;

over-aII : R”CH-COO-

CO?

in the

Conversely, we may expIain the effect on neutrality arising when NHJ+ is substituted by the kidney for urea as an excretory product, by noting that this substitutes a hydrogen-ionbearing product for a neutral product of protein catabolism. In a sense renal NH,+ synthesis diminishes the extent to which reactions equivaIent to (3) proceed metaboIicaIIy. AIthough such reactions normalIy occur in the course of protein catabolism, their acidifying effect is more or less equivaIentiy opposed by the conversion of the carboxylate part of each amino acid into CO,: RNH,+ 2

formed

As long as the metaboIic

(4)

The acidosis may be transient if the Iatter stage can catch up with the earlier one, but if acetoacetate is lost into the urine, the H+ is left behind for other modes of disposal. hlany substances introduced therapeutically to modify the state of neutrality aIso use the metabolic machinery to accomplish their purinfused sodium lactate poses. For exampIe, solutions suppIy Iactate for conversion to CO2 and water, with the inevitable removal of a hydrogen ion. Ingested ammonium chIoride acidifies the organism because the Iiver cIears it efhcientIy from the porta circulation and converts it to urea by a hydrogen-ion producing reaction: 2NtI4+

ReguIation

Ot + $$ urea + carbon dioxide + water

CO? + Hz0 + HzC03 -+ Hi + HCO:,-

I NH,,+ (6)

This necessity explains why restoring the extracellular fluid volume with NaCI soIution appears to have an acidifying effect, which cannot of course be attributed to an acidifying effect of chloride ion. This step actuaIIy exposes an existing H+ excess that has been hidden by the shrunken voIume of the extracehular fluid.

Perhaps the effects of HCO,- administration and excretion on neutrahty may to an advantage be considered in the same genera1 way so far considered. In this case we aIso have a transient reIease of Hf during the passage of 287

Christensen we need the assistance of the Iogarithmic system; and yet when we accept that assistance, we put ourseIves in a position in which everything seems indirect. ARNOLD S. RELMAN (Boston, Mass.): We reaIIy are indebted to Dr. Christensen for this way of Iooking at acid-base balance. I am one who having been educated in the cIassic way of thinking about acid-base baIance, had to struggIe hard to understand why sodium was considered a “base” and chIoride an “acid.” I believe that Dr. Christensen’s written work on this subject over the Iast few years has done more than aImost anything else I know of to restore some reason to this fieId. It is true that all the great peopIe in this fieId early in this century reaIIy understood the subject; however, I think the expIoration of mechanisms and certainIy the teaching of mechanisms was greatIy hampered by poor terminoIogy. So much so, that the mechanisms themseIves became obscure and, as Dr. Christensen says: “Writers of some of the recent medica Iiterature scarceIy concede that the hydrogen ion is invoIved in neutraIity contro1.” I think that Dr. Christensen’s writings on this subject have gone far to remedy this situation. To those who do not know about his IittIe book caIIed, “Diagnostic Biochemistry,” I enthusiasticaIIy recommend it to their attention. This, I think, is the most succinct, readabIe and reasonable description of acidbase baIance that is to be found published in English today. FRANCIS D. MOORE (Boston, Mass.): I think Dr. Christensen reaIly answered the question concerning hydrogen ion concentration. With many zeros in front of a number, it is convenient to have a soIid integer that is on a Iogarithmic scaIe. However, in gastric physioIogy, it is wise to remember that gastric secretion as it Ieaves the parieta1 cell has a pH of I, which means that the hydrogen ion concentration is I00 miIIiequivaIents per Iiter. If it gets mixed with antral secretion, it may drop to 50 or IO; but at that Iow pH range, one is deaIing with hydrogen-ion concentrations which are in the same genera1 order of magnitude as that of which we are accustomed to thinking in connection with famiIiar cations and anions. That is why peopIe with a pyloric obstruction become alkalotic so fast.

More universaIIy the hydrogen ion excesses of metaboIic acidosis have been partIy hidden by a prior respiratory correction of neutrahty: H+ + HCOI- --) H&OS -+ H20 + CO2 This reaction must aIso be reversed to regenerate the Iost HC03-, before the elimination of the H+ excess may be considered uItimate. I beIieve we must focus our attention on the hydrogen ion and the substances that reIease it and bind it, if we are to think accurateIy and cIearIy about the contro1 of neutraIity. This is by no means to say that we can interpret each situation by measurements onIy of hydrogenion concentration, but rather that we do not accurateIy understand neutraIity contro1 if we ignore the hydrogen ion and its measurement. DISCUSSION JOHN J. BYRNE (Boston, Mass.): There is an interesting articIe in a recent issue of the .TournaZ of Clinical Research written by Huckabee concerning our reliance on pH measurements. He suggests that we use hydrogen ion measurement just as we do for chlorides and potassium and that they be read off as microequivaIents or micromilliequivaIents. I suppose it will be a Iong time before we get the pH out of our measuring system, but I wouId like to ask for comments concerning this proposaI. H. N. CHRISTENSEN (Ann Arbor, Mich.): CertainIy this system is a barrier to our thinking but it is a built-in diffIcuIty. Hydrogen ion concentrations with which we deaI are so Iow that we cannot actuaIIy measure them except by their side effect on eIectrodes or on other sensitive systems. We cannot titrate a concentration of Io+ moIar directIy by any way that I know and discover the hydrogen ion that is present. I suspect that the important thing is to operate between pH and hydrogen ion concentration so reguIarIy during training that this mathematicaIIy diffIcuIt situation does not constitute the barrier that it tends to be. I see no way out of it at the present time. Nature has set the exponentia1 reIationship for us; hence,

288