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Metabolic Acidosis: Acid Gain Types


Introduction

The focus in this chapter is on metabolic acidosis due to the accumulation of acids. Two disorders that can cause this type of metabolic acidosis are not discussed in this chapter. Ketoacidosis was discussed in Chapter 5 . Metabolic acidosis caused by hippuric acid production from the metabolism of toluene in patients who sniff glue was discussed in Chapter 4 , because the hippurate anion is uniquely secreted into the urine, resulting in a hyperchloremic form of metabolic acidosis due to an indirect loss of NaHCO 3 .

It is important to recognize that the term metabolic acidosis is not a specific diagnosis—rather, it is a disorder that can be the result of a number of disease processes. Therefore, the clinician must determine the basis for metabolic acidosis in each patient because this has major implications for the management of the patient. Even in a single category such as L-lactic acidosis, there are different pathophysiologic mechanisms that may lead to the accumulation of L-lactic acid; hence, a definitive diagnosis is needed to address the specific underlying pathophysiology in the an individual patient.

Objective

  • ▪

    To provide an understanding of the pathophysiology of the different disease processes that may cause metabolic acidosis due to the accumulation of acids.

  • ▪

    To provide an approach to the clinical diagnosis and management of patients with the different disease processes that may cause metabolic acidosis due to the gain of acids, emphasizing that the presence of metabolic acidosis is a red flag to alert the physician about an ominous danger to the patient.

Case 6-1: Patrick Is in for a Shock

Patrick, a large, muscular man, has a long history of alcohol abuse. He was perfectly well until he drank a solution containing an unknown substance about 6 hours ago. In the past hour, he began to feel very unwell. He denied blood loss, vomiting, or diarrhea. His clinical condition deteriorated very quickly. On presentation to the emergency room, his respirations were rapid and deep, his blood pressure was 80/50 mm Hg, his pulse rate was 150 beats per minute, and his jugular venous pressure was flat. His electrocardiogram revealed changes due to hyperkalemia with tall, peaked T waves. His arterial blood gas revealed a pH of 7.20 and a PCO 2 of 25 mm Hg. The concentration of bicarbonate (
HCO 3 − ) ions in plasma (
P HC O 3 ) in a venous blood sample was 11 mmol/L. Other laboratory data are provided in the following table. Shortly after he was given intravenous calcium gluconate for the emergency treatment of hyperkalemia, his blood pressure rose and he felt much better.

P Na mmol/L 143 P K mmol/L 6.3
P Cl mmol/L 99
P HC O 3 		mmol/L 11
P Glucose mg/dL (mmol/L) 180 (10) P Albumin g/dL (g/L) 4.5 (45)
P Creatinine mg/dL (μmol/L) 1.8 (160) BUN
P Urea 		mg/dL
mmol/L		 8.4
3.0
P Ca (total) mg/dL (mmol/L) 10 (2.5) P L-lactate mmol/L 2.0

Questions

Judging from the time frame for his illness, what is (are) the likely cause(s) of metabolic acidosis?

  • Why did his blood pressure fall so precipitously?

  • Why did he have hyperkalemia?

  • Why did the administration of intravenous calcium cause a rapid recovery?

Abbreviations

  • P Na , concentration of sodium (Na + ) ions in plasma

  • P K , concentration of potassium (K + ) ions in plasma


  • P HC O 3     , concentration of bicarbonate (
    HCO 3 −     ) ions in plasma

  • PCl, concentration of chloride (Cl − ) ions in plasma

  • P Glucose , concentration of glucose in plasma

  • BUN, concentration of urea nitrogen in blood

  • P Urea , concentration of urea in plasma

  • P Creatinine , concentration of creatinine in plasma

  • P Albumin , concentration of albumin in plasma

  • P Ca , concentration of calcium ions in plasma

  • P Anion gap , anion gap in plasma

  • P Osm , plasma osmolality

  • P Osm gap , osmolal gap in plasma

  • EABV, effective arterial blood volume

  • ATP, adenosine triphosphate

  • ADP, adenosine diphosphate

  • ECF, extracellular fluid

  • ICF, intracellular fluid

  • BBS, bicarbonate buffer system

Case 6-2: Metabolic Acidosis Associated With Diarrhea

One week ago, this 40-year-old man began to have several bouts of diarrhea during a trip abroad. He was treated with an antimotility drug and an antibiotic. In the past 24 hours, however, his diarrhea has increased. His only intake has been popsicles to satisfy his desire for cold liquids. On physical examination, he appeared very ill and was confused. He had poor balance and an ataxic gait. He did not have signs of an appreciable decrease in his effective arterial blood volume (EABV).

His abdomen was distended and bowel sounds were scanty. There were no masses or enlarged organs. Acetone was not detected on his breath, and the urine test for ketones was negative. His arterial blood gas revealed a pH of 7.22 and a PCO 2 of 27 mm Hg. His
P HC O 3 in a venous blood sample was 11 mmol/L. Other laboratory data from measurements in a venous blood sample are provided in the following table.

P Na mmol/L 138 P K mmol/L 3.8
P Cl mmol/L 101 P Glucose mg/dL (mmol/L) 108 (6)
P Albumin g/dL (g/L) 3.8 (38) P Osm mosmol/kg H 2 O 289
BUN mg/dL 14 P Creatinine mg/dL 1.2
P Urea mmol/L 5.0 P Creatinine μmol/L 106

Question

What is the cause for the metabolic acidosis in this patient?

Case 6-3: Severe Acidemia in a Patient With Chronic Alcoholism

A 52-year-old man presented to the emergency room with abdominal pain, visual disturbances, and shortness of breath. He had a history of drinking excessive amounts of alcohol on a regular basis. He admitted to drinking approximately 1 L of vodka the day before but denied ingesting any other substances. During the 24 hours before admission, he had not eaten at all. In the 5 hours before his admission, he had several bouts of vomiting and did not drink any alcohol. His dietary intake has been generally very poor over the last several months because he had no appetite.

On physical examination, he was conscious and oriented. His respiratory rate was rapid (40 breaths per minute). His pulse rate was also rapid (150 beats per minute), and his blood pressure was 120/58 mm Hg. Neurological examination was unremarkable. His urine tested strongly positive for ketones. His initial laboratory results on admission to the emergency department are shown in the following table. The plasma pH and PCO 2 are from an arterial blood sample; the other measurements are from a venous blood sample.

P Na mmol/L 132 pH 6.78
P K mmol/L 5.4 PCO 2 mm Hg 23
P Cl mmol/L 85 P Glucose mmol/L 3.0

P HC O 3 		mmol/L 3.3
P Anion gap mEq/L 44 P Albumin g/L 36
P Osm mOsm/L 325 P Osm gap mosmol/kg H 2 O 42
Hematocrit 0.46

Question

What dangers may be present on admission or arise during therapy?

Part A

General Considerations

Major threats in the patient with metabolic acidosis

There are a number of threats for the patient with metabolic acidosis caused by added acids, depending on the underlying cause of the metabolic acidosis ( Table 6-1 ). The emphasis in therapy should be to deal with the underlying cause of the metabolic acidosis rather than just focusing on how to deal with the H + ion load. For example, although L-lactic acid may be produced at an extremely rapid rate during hypoxia, an energy crisis because of failure to regenerate adenosine triphosphate (ATP) in vital organs, rather than the acidemia per se, is the most important danger for the patient. In a patient with methanol or ethylene glycol intoxication, toxic aldehydes formed during metabolism of these alcohols pose the major danger to the patient. In patients with pyroglutamic acidosis, the major danger is accumulation of reactive oxygen species (ROS) due to depletion of glutathione. In patients with D-lactic acidosis, a number of compounds produced by intestinal bacteria can cause cerebral dysfunction. In patients with metabolic acidosis due to end stage kidney disease, the danger may be a cardiac arrhythmia because of associated hyperkalemia.

TABLE 6-1
Threats to Life Associated With the Cause of the Addition of Acids
Although other emergencies may be present, only those that are specific to the cause of the metabolic acidosis are included in this table.

Condition Major Threat

  • L-Lactic acidosis due to hypoxia

  • Inadequate delivery of O 2 to vital organs, causing depletion of ATP

  • Diabetic ketoacidosis in children

  • Cerebral edema

  • Alcoholic ketoacidosis with thiamin deficiency

  • Wernicke’s encephalopathy

  • Toxin-induced metabolic acidosis (e.g., methanol)

  • Toxic aldehyde metabolites (e.g., formaldehyde)

  • Metabolic acidosis with a high P K (e.g., renal failure)

  • Cardiac arrhythmia

  • Metabolic acidosis with a low P K (e.g., glue sniffing)

  • Cardiac arrhythmia, respiratory failure

  • Pyroglutamic acidosis

  • Accumulation of reactive oxygen species due to depletion of glutathione

Buffering of H + Ions in a patient with metabolic acidosis

Binding of H + ions to proteins in cells alters their charge, shape, and perhaps their functions. This may be particularly detrimental if it occurs in cells of vital organs (e.g., the brain and heart). To prevent this “bad” form of buffering of H + ions, H + ions must be “forced” to bind to
HCO 3 − ions in the extracellular fluid (ECF) and intracellular fluid (ICF) compartments of skeletal muscle because this is where the bulk of the bicarbonate buffer system (BBS) exists. For this to occur, the PCO 2 in capillary blood of skeletal muscle must be low. There are two requirements to achieve a low PCO 2 in capillary blood of skeletal muscle. First, an appropriate fall in arterial PCO 2 in response to the effect of acidemia to stimulate the respiratory center. Second, a high enough blood flow rate to skeletal muscle relative to their rate of production of CO 2 . If this fails to titrate the H + ion load, the degree of acidemia may become more pronounced and more H + ions may bind to proteins in the ECF and ICF in other organs, including the brain (see Figure 1-7 ). Because of autoregulation of cerebral blood flow, however, it is likely that the PCO 2 in brain capillary blood will not change appreciably unless there is a severe degree of contraction of the EABV. Hence, the BBS in the brain will continue to titrate much of this large H + ion load. Considering the limited content of
HCO 3 − ions in the brain, and that the brain receives a relatively larger proportion of blood flow, there is a risk that more H + ions will bind to proteins in the brain cells, further compromising their functions.

Therefore, an important aim in therapy in patients with metabolic acidosis is to improve ventilation and to restore blood flow to skeletal muscles to lower their capillary PCO 2 (which is reflected by the PCO 2 in their venous blood). At the usual rates of blood flow and metabolic work at rest, the PCO 2 in venous blood of skeletal muscle is about 46 mm Hg—that is, ∼6 mm Hg greater than the arterial PCO 2 . If the blood flow rate to the skeletal muscles declines because of a low EABV, the brachial venous PCO 2 will be increased to >6 mm Hg higher than the arterial PCO 2 . It is our opinion that in patients with metabolic acidemia and a low EABV, enough saline should be administered to increase the blood flow rate to muscle to restore the differences between the brachial venous PCO 2 and the arterial PCO 2 to its usual value of ∼6 mm Hg.

Issues in diagnosis

Accumulation of acids (H + + A − ) in the ECF compartment will result in the loss of
HCO 3 − ions and the gain of new anions. This addition of new anions can be detected by their electrical presence. Because electroneutrality must be maintained, the sum of all the valences of cations and the sum of all the valences of anions in plasma must be equal. For convenience, however, one need not measure the concentrations of all the cations and all the anions in plasma, but rather that of the major cation in plasma, sodium (Na + ) ions, and the major anions in plasma, chloride (Cl − ) and
HCO 3 − ions. The term plasma anion gap (P Anion gap ) is used for the difference between the concentration of Na + ions and the sum of the concentrations of Cl − ions and
HCO 3 − ions in plasma. This difference reflects the usual excess of the other anions in plasma over that of the other cations in plasma, which is largely due to the net anionic valence on plasma proteins, principally plasma albumin (P Albumin ). If the difference is larger than the “normal” value of the P Anion gap , then other anions are present in plasma. Note, however, that because of differences in laboratory methods (e.g., measurement of P Cl ), there is a large difference in the mean value for the P Anion gap reported by different clinical laboratories. Furthermore, regardless of the laboratory method used, there is a wide range for the normal values of the P Anion gap . Although it is imperative that the clinician knows the normal values of the P Anion gap for his or her clinical laboratory, it would be difficult to know what the individual patient’s baseline P Anion gap was within the wide range of normal values. Another pitfall in the use of the P Anion gap is the failure to correct for the net negative valence attributable to the most abundant unmeasured anion in plasma, albumin. This adjustment should be made for a fall (or an increase) in the P Albumin . The P Anion gap is reduced (or increased) by 2.5 mEq/L for each 1g/dL (10 g/L) decrease (or increase) in the P Albumin . One must also be aware of other causes for a spurious reduction in the P Anion gap (e.g., cationic proteins in a patient with multiple myeloma, lithium intoxication).

If metabolic acidosis develops over a short period of time, the likely causes are overproduction of L-lactic acid (e.g., shock, ingestion of alcohol in a patient with thiamin deficiency) or ingestion of acids (e.g., metabolic acidosis due to ingestion of a large quantity of citric acid).

Disorders causing metabolic acidosis due to added acids are often associated with a marked decrease in the EABV. If not, suspect a toxin-induced form of metabolic acidosis (methanol or ethylene glycol), renal failure, or L-lactic acidosis due to causes other than tissue hypoxia (discussed in the following).

Part B

Specific Disorders

L-lactic acidosis

To understand the pathophysiology that leads to the development of L-lactic acidosis, we begin the discussion with a synopsis of the biochemistry of glucose oxidation. This is followed by a description of the biochemistry of the process that leads to the accumulation of L-lactic acid.

Synopsis of biochemistry of glucose oxidation in skeletal muscles

The process of oxidation of glucose can be divided into three phases: the first is glycolysis, the second is the citric acid cycle, and the third is the electron transport chain ( Figure 6-1 ):

Abbreviations

  • NAD + , nicotinamide adenine dinucleotide

  • NADH,H + , reduced form of NAD +

  • FAD, flavin adenine dinucleotide

  • FADH 2 , hydroxyquinone form of FAD

  • ADP, adenosine diphosphate

  • AMP, adenosine monophosphate

  • CoA-SH, coenzyme A with functional sulfhydryl group

  • GDP, guanosine diphoshate

  • GTP, guanosine triphoshate

  • Pi, inorganic phosphate

  • 1.

    Glycolysis: In glycolysis, one molecule of glucose is split into two molecules of pyruvate. Oxygen is not required in the process. Two molecules of ATP are utilized in the initial reactions in glycolysis, which are catalyzed by kinases hexokinase and phosphofructokinase-1 (PFK-1). Four molecules of ATP are ultimately generated; hence, there is net generation of two molecules of ATP. Also 2 molecules of nicotinamide adenine dinucleotide (NAD + ) are converted to its reduced form, NADH,H + ( Eqn 1 ).

    Glucose + 2 ATP + 2 NAD + → 2 Pyruvate + 4 ATP + 2 NADH,H +

    • PFK-1 is a key regulatory enzyme in glycolysis in skeletal muscle. PFK-1 catalyzes an important committed step in the process of glycolysis: the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and adenosine diphosphate (ADP). The activity of this enzyme is under direct allosteric regulation by ATP (i.e., when concentration of ATP in the cytosol is high as a result of low metabolic demand, PFK-1 is inhibited, causing flux through glycolysis to be low. In contrast, when the concentration of ATP in cytosol is low, PFK-1 is activated and flux through glycolysis is high to replenish the pool of ATP). Notwithstanding, there is little variation (<10%) in the concentration of ATP in the cytosol of skeletal muscle between resting condition and vigorous exercise, yet flux in glycolysis can increase by more than 100-fold. Therefore, the signal related to a change in the ATP concentration must be amplified. In more detail, hydrolysis of ATP to perform biological work results in formation of ADP. ADP is converted back to ATP in a near-equilibrium reaction catalyzed by the enzyme adenylate kinase (also known as myokinase), and adenosine monophosphate (AMP) is generated ( Eqn 2 ).

      2 ADP → ATP + AMP

    • Because the concentration of ATP in muscle is about 50 times higher than the concentration of AMP and about 10 times higher than the concentration of ADP, a small decrease in the concentration of ATP results in a large increase in the concentration of AMP. Therefore, the signal of a decrease in the concentration of ATP is markedly amplified via an increase in AMP concentration to produce a large increase in PFK-1 activity.

    • To maintain a high flux in glycolysis, NADH,H + that is produced must be converted back to NAD + . Under aerobic conditions, NADH,H + is oxidized in mitochondria to NAD + . Because the inner mitochondrial membrane lacks an NADH,H + transport protein, the electrons from cytosolic NADH,H + are transported into the mitochondria using the malate/aspartate shuttle. Under anaerobic conditions, NADH,H + can be converted to NAD + in the cytosol, in an equilibrium reaction in which pyruvate is reduced to L-lactate, catalyzed by the enzyme lactate dehydrogenase (LDH) ( Eqn 3 ).

      Pyruvate + NADH,H + → Lactate − + NAD +

  • 2.

    Citric acid cycle: Pyruvic acid is transported into the mitochondria by a monocarboxylic acid cotransporter. Once in the mitochondrial matrix, pyruvate is converted into acetyl-CoA by the multienzyme complex pyruvate dehydrogenase (PDH). In this process, one molecule of CO 2 is produced and one NAD + is reduced to NADH,H + ( Eqn 4 ). A derivative of thiamin is an important cofactor for PDH.

    Pyruvate + CoA-SH + NAD + → Acetyl-CoA + CO 2 + NADH,H +

    • Acetyl-CoA (a two-carbon compound) combines with oxaloacetate (a four-carbon compound), to form citrate (a six-carbon compound), in a reaction catalyzed by the enzyme citrate synthase ( Eqn 5 ).

      Acetyl-CoA + Oxaloacetate → Citrate

    • Citrate then enters the citric acid cycle (also called the tricarboxylic acid cycle or the Krebs cycle), where it undergoes a series of reactions, catalyzed by a number of enzymes, which leads to the oxidation of the acetyl group into two CO 2 molecules and the regeneration of the four-carbon molecule oxaloacetate. In this process, three molecules of NAD + are reduced to three molecules of NADH,H + , one molecule of flavine adenine dinucleotide (FAD) is made into its hydroxyquinone form FADH 2 , and one molecule of guanosine diphosphate (GDP) and one molecule of inorganic phosphate (Pi) are made into one molecule of guanosine triphosphate (GTP) (the latter is equivalent to the conversion of one molecule of ADP and one molecule of Pi into one molecule of ATP) ( Eqn 6 ). Because two molecules of pyruvate are produced from one molecule of glucose in glycolysis, two molecules of ATP are regenerated per one molecule of glucose in the citric acid cycle.

      Acetyl-CoA + Oxaloacetate + 3 NAD + + 1 FAD + 1 GDP + Pi → 2 CO 2 + 3 NADH,H + + 1 FADH 2 + 1 GTP (ATP) + Oxaloacetate

    • Although the citric acid cycle does not require O 2 , it can only take place in the presence of O 2 , because it requires the regeneration of NAD + and FAD, which takes place in the process of oxidative phosphorylation.

      ATP Regeneration from Oxidation of NADH,H + and FADH 2

      • This approximation of the rate of ATP regeneration from oxidation of NADH,H + and FADH 2 takes into account the possible leak of electrons from the electron transport chain.

      • Ten molecules of NADH,H + and two molecules of FADH 2 are produced per molecule of glucose that undergoes metabolism in glycolysis and the citric acid cycle.

      • Oxidation of the electrons from 10 molecules of NADH,H + and 2 molecules of FADH 2 in the electron transport chain leads to regeneration of 28 molecules of ATP.

      • Oxidation of 1 molecule of glucose can lead to the regeneration of 32 molecules of ATP (2 molecules in glycolysis, 2 molecules in the citric acid cycle, 28 molecules in the electron transport chain). This is summarized in Figure 6-1 .

  • 3.

    Electron transport chain: Oxidation of the electrons from NADH,H + and those from FADH 2 by O 2 is the major process used by cells to regenerate ATP (see Chapter 5 ). Flow of electrons through the electron transport chain (coenzyme Q, flavin mononucleotide [FMN] and flavin adenine dinucleotide [FAD], and ultimately to cytochrome C) from electron donors (NADH,H + and FADH 2 ) to electron acceptors (O 2 ) releases energy. This energy is used to pump H + ions from the mitochondrial matrix through the inner mitochondrial membrane. This creates a very large electrical (∼150 mV) and a smaller chemical (equivalent to ∼30 mV) driving force for H + ion re-entry. This energy is recaptured as H + ions flow through the H + channel portion of the H + -ATP synthase in the inner mitochondrial membrane, which is coupled (linked) to ATP regeneration, providing that ADP and inorganic phosphate (Pi) molecules are available inside these mitochondria. Oxidation of one molecule of NADH,H + leads to regeneration of 2.5 molecules of ATP, while only 1.5 molecules of ATP are regenerated from oxidation of one molecule of FADH 2 (see margin note). Hence, there is net regeneration of approximately 32 mmol of ATP from the oxidation of one molecule of glucose.

    • The process of oxidation of glucose can be summarized as shown in Eqn (7) .

      Glucose (C 6 H 12 O 6 ) + 6 O 2 + 32 (ADP + Pi) → 6 CO 2 + 6 H 2 O + 32 ATP

    • In the cytosol, energy needed to perform biological work (e.g., ion pumping by Na-K-ATPase) is provided by hydrolysis of the terminal high-energy bond of ATP. This results in formation of ADP. ADP enters the mitochondria on the adenine nucleotide translocator in exchange for ATP, which is produced in the mitochondria in coupled oxidative phosphorylation in the electron transport chain.

Figure 6-1, Biochemistry of Oxidation of Glucose.

Synopsis of the biochemistry of l-lactic acidosis

A rise in the concentration of L-lactate – anions and H + ions can be caused by an increased rate of production and/or a decreased rate of removal of L-lactic acid. Although both of these mechanisms are involved in most cases, usually one mechanism predominates.

Increased production of l-lactic acid

Increased production of L-lactic acid occurs under conditions in which the rate of regeneration of ATP in mitochondria is largely insufficient to meet the requirement for ATP to perform its biological work ( Figure 6-2 ). Under these conditions of diminished rate of regeneration of ATP, the concentration of ADP in the cytosol in cells rises. As stated previously, when ADP is converted back to ATP in the near-equilibrium reaction catalyzed by the enzyme adenylate kinase, AMP is generated ( Eqn 2 ). The increase in AMP concentration produces a robust signal that leads to a large increase in PFK-1 activity and hence the flux in glycolysis in muscle is augmented. The accumulation of pyruvate in the cytosol, coupled with an increase in NADH,H + /NAD + ratio, drives the equilibrium reaction catalyzed by the enzyme LDH, in which pyruvate is reduced to L-lactate and NADH,H + is converted to NAD + . Contrary to common belief, glycolysis is not a metabolic pathway that causes net production of H + ions (count the valences in the following equations individually and then together to see where H + ions are produced). One can see that the hydrolysis of ATP 4− to perform biological work is what produces the H + ions, rather than the conversion of one molecule of glucose to two L-lactate anions ( Eqns 8 and 9 ).


Work + 2 ATP 4 − → 2 ADP 3 − + 2 H + + 2 H P O 4 2 −

Glucose + 2 AD P 3 − + 2 HP O 4 2 − → 2 AT P 4 − + 2 L − lactate −

Figure 6-2, Biochemistry of L -Lactic Acid Production.

Although only 2 mmol of ATP are regenerated per mmol of glucose in glycolysis (versus approximately 32 mmol of ATP when 1 mmol of glucose is oxidized), the rate of ATP production by glycolysis can be 100 times faster than that in oxidative phosphorylation. The price to pay, however, is the production of 1 mmol of L-lactic acid per 1 mmol of ATP regenerated. An increase in H + ion concentration inhibits PFK-1. Although this minimizes the drop in intracellular pH, there is a huge price to pay because this may lead to a critical shortage of energy, especially in cells of vital organs (e.g., the brain).

Decreased removal of l-lactic acid

In normal physiology, glycolysis is an obligatory pathway for the regeneration of ATP in red blood cells because they lack mitochondria; therefore, red blood cells always produce L-lactic acid. L-Lactic acid may be also produced by fast-twitch muscle fibers during muscle contraction and by enterocytes when glucose and amino acids are absorbed. This load of L-lactic acid produced under normal circumstances is removed via gluconeogenesis in the liver. Hence, under conditions of severe loss of liver tissue (e.g., due to hepatitis, shock liver, infiltration by tumor cells), L-lactic acidosis may develop. In this setting, L-lactic acid accumulates and the level of L-lactate anions in plasma rises until the level of pyruvate in hepatocytes in the remaining liver tissue is sufficient to saturate the critical enzymes in gluconeogenesis (pyruvate carboxylase [PC] and phosphoenolpyruvate carboxykinase [PEPCK]) with their substrates to drive the reactions catalyzed to their maximum velocity. When this level of L-lactate anions in plasma is reached, all the L-lactic acid produced is removed, and therefore a chronic steady state develops.

There are two major ways to remove L-lactic acid: oxidation and conversion to glucose in the liver and the kidney ( Figure 6-3 ). In both processes, the first step is the conversion of L-lactate into pyruvate in the equilibrium reaction catalyzed by LDH ( Eqn 10 ). An important point to emphasize here is that one cannot overcome a rapid rate of production of lactic acid by enhancing its rate of removal.

L-lactate − + NAD + → Pyruvate + NADH,H +

Figure 6-3, Biochemistry of L -Lactic Acid Removal.

Oxidation of L-lactic acid

Pyruvic acid is transported into the mitochondria via a monocarboxylic acid cotransporter and is then metabolized by PDH into acetyl-CoA. Metabolism of acetyl-CoA follows the pathway described previously. To oxidize 1 mmol of L-lactic acid, 3 mmol of oxygen must be consumed, and 16 mmol of ATP are formed in coupled oxidative phosphorylation. Therefore, if (theoretically) all organs could be persuaded to oxidize L-lactic acid to yield 100% of their requirement to regenerate ATP, only 4 mmol of L-lactic acid could be oxidized per minute at rest (O 2 consumption is 12 mmol/min at rest).

It is important to note the large imbalance of the rate of ATP regeneration when H + ions are produced in glycolysis and when they are removed via the oxidation of L-lactic acid. While 18 mmol of H + ions are produced per 18 mmol of ATP regenerated in glycolysis, only 1 mmol of H + ions is removed when 16 mmol of ATP are regenerated via oxidation of 1 mmol of L-lactic acid.

Gluconeogenesis

L-lactic acid can be made into glucose in the liver and in the kidney cortex. L-Lactate is converted to pyruvate as shown in Eqn 10 . Pyruvic acid is transported into the mitochondria, where it is metabolized into oxaloacetate by the enzyme pyruvate carboxylase. Oxaloacetate is then reduced to malate, which is transported into the cytosol by the malate transporter. In the cytosol, malate is made back into oxaloacetate. Oxaloacetate then feeds into the gluconeogenic pathway via its conversion to phosphoenolpyruvate by the biotin (vitamin B 2 )-requiring enzyme PEPCK. The conversion of 2 mmol of pyruvate to 1 mmol of glucose uses 6 mmol of ATP.

Because the liver and the kidneys each consume 2 mmol of O 2 per minute, they both regenerate a total of 24 mmol of ATP per minute. Thus, the maximum rate of L-lactic acid removal via gluconeogenesis is close to 4 mmol/min, even if all the available ADP in the liver and the kidneys is used only in gluconeogenesis and no other biologic work is performed, which is extremely unlikely.

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