LACTIC ACIDOSIS- PART 1

"Variability is the law of life, 

And as no two faces are same, so no two bodies are alike,

And no two individuals react alike and behave alike,

Under the abnormal  conditions, which we know as disease."

                                                                      - William Olser

Lactic acidosis is caused by accumulation of lactate and protons in the body. It is often associated with poor clinical outcomes. The impact of lactic acidosis is determined by its severity, duration and the causative pathophysiology. Sustained hyperlactatemia in hospitalized patients with diverse disorders is associated with a large increase in mortality, regardless of status with respect to shock or hypotension. 

Hyperlactatemia is not the same as lactic acidosis.

Under physiological pH lactic acid is 99 percent dissociated into lactate and [H⁺]. As per steward’s strong ion difference (SID) concept, acid base balance is determined by the independent effect of CO₂, concentration of weak acids and strong ion difference. Bicarbonate (HCO₃) simply acts as buffer and has no direct role in determining acid base balance.

Lactate acts as strong anion, but not the only strong anion that affects acid base balance.
Therefore, development of lactic acidosis is dependent upon magnitude of hyperlactatemia, buffering capacity of body and other coexisting factors determining acid base balance. Thus hyperlactatemia can be associated with acidosis, neutral pH or alkalosis.

Although traditionally hyperlactatemia is attributed to tissue hypoxia and is considered a marker of poor organ perfusion, however it can occur in presence of adequate oxygen, and various other pathophysiological conditions.

Daily production of lactate amount to 20 mmol/kg (approximately 1500 mmol). In human body Lactate is produced by several tissues but muscle is the highest producer. Under normal conditions, lactate is rapidly metabolized by liver (60%), with a small help from kidneys (30%).

During evolutionary process, Glycolysis evolved under condition of low atmospheric oxygen, converting glucose into pyruvate with generation of 2 ATPs. However, it is was not very efficient energy production method. 

With the rise in atmospheric oxygen level, mitochondria came into existence, as an energy efficient measure, producing 36 ATPs from single glucose molecule through Krebs cycle and oxidative phosphorylation.

Lactate metabolism (Production and consumption) in body is governed by following equation in glycolysis pathway:
                                 Pyruvate + NADH + H+ ←→ Lactate + NAD+
This reaction is catalyzed by lactate dehydrogenase (LDH).

Earlier it was proposed that during hypoxia, pyruvate produced in glycolysis, accumulates and converted to lactate, as waste product. This was termed as anaerobic glycolysis.

But over the years, it has been shown that lactate is produced, even in presence of adequate oxygen, as during various disease states. This has been termed as aerobic glycolysis.

Aerobic glycolysis is an effective, though inefficient method of rapid energy production. Rate of glycolysis can increase, manifold than oxidative phosphorylation. Therefore in conditions requiring huge amount of energy, as in stress, lactate acts as a critical buffer that facilitates glycolysis to accelerate. 

Thus lactate is not a waste product of metabolism, rather it is a dynamic metabolite. It can be converted into glucose, the primary energy fuel, or utilized as preferred energy fuel in various vital organs like skeletal muscles, liver, heart, neurons and kidney.

Vehicles for lactate metabolism are Cori cycle (in liver and kidney) and lactate shuttle (in skeletal muscle, heart and neurons).

Cori cycle converts lactate into pyruvate and then into glucose through gluconeogenesis.

Lactate shuttle is involved in transporting lactate from cytosol (where it is produced) into mitochondria. It is then oxidized into pyruvate, which enters into krebs cycle.

Lactates shuttle also transports lactate from one tissue to other, where it is oxidized to produce energy.

When lactate is oxidized for energy production, it produces equivalent amount of energy as glucose.

Increased lactate production is probably an adaptive response to stress, evolved as survival advantage. In healthy condition heart utilized free fatty acids as fuel, for 70-90 percent of its energy needs. However under stress, cardiac muscles start using lactic acid for major energy production.

It has been demonstrated in animal models that, inhibition of lactate production by beta adrenergic blockers, and acceleration of Lactate clearance by dichloroacetate, resulted in cardiovascular compromise and early mortality.

In another study infusions of sodium lactate, improved cardiac performance in patients with both septic and cardiogenic shock.

Studies have shown that epinephrine is associated with increased lactate level, despite increased cardiac output and oxygen delivery. Rise in lactate, after epinephrine infusion is associated with higher survival. Patients who did not show this response, had increased mortality.

Mechanism of hyperlactatemia in stress is multifactorial. Inhibition of pyruvate dehydrogenase, activation of Na/K-ATPase pump and mitochondrial dysfunction leads to acceleration of glycolysis and inhibition of krebs cycle/ oxidative phosphorylation.

Stressed induced epinephrine release stimulates Na/K ATPase activity, leading to increased glycolysis.

Hypoxia, epinephrine, cytokines and thiamine deficiency impair pyruvate dehydrogenase, responsible for pyruvate metabolism in krebs cycle.

Hypoxia inhibits mitochondrial oxidative phosphorylation.

Lactic acidosis associated with sepsis is due to hypoxia, hyperadrenergic state, microcirculatory derangement and mitochondrial dysfunction. In other words both type A and type B lactic acidosis coexists in sepsis.

Dialysis (hemofiltration) can remove only 3% of total body lactate. Therefore dialysis can reduce serum lactate, only if culprit derange, pathophysiology is corrected.

Serum lactate can be measured from arterial or venous sample, as both are interchangeable.

Lactate exists in 2 isomers: L-lactate and D-lactate.  

L-lactate is produced in human during cellular metabolism as described before.

D-Lactate is produced by bacteria in the human colon on exposure to large amounts of unabsorbed carbohydrates. In the setting of alteration in the intestinal flora and a high carbohydrate load (such as in short bowel syndrome), there will be an excess production of D-lactate, which can cross into the bloodstream and potentially cause neurologic symptoms.  

Traditionally lactic acidosis is classified as type A and type B lactic acidosis.

Type A lactic acidosis is due to anaerobic glycolysis (inadequate oxygen delivery and poor perfusion states).

Type B lactic acidosis is seen with aerobic glycolysis (adequate oxygen delivery and optimal perfusion states). It is associated with stress, underlying disease, drugs and genetic enzyme deficiency disorders.


Pyruvate to lactate ratio may differentiate between type A and type B lactic acidosis. Normal pyruvate: lactate ratio is 10:1. An increase in this ratio suggests type A lactic acidosis, whereas it is normal in type B lactic acidosis.

Central venous saturation (SCVO₂) may also differentiate between types of lactic acidosis. A low SCVO₂ suggests type A lactic acidosis, while a normal value indicates type B lactic acidosis.