Each day the body has an excess production of about 1500 mmols of lactate (about 20 mmols/kg/day) which enters the blood stream and is subsequently metabolised mostly in the liver. This internal cycling with production by the tissues and transport to and metabolism by the liver and kidney is known as the Cori cycle. This normal process does not represent any net fixed acid production which requires excretion from the body.

 

All tissues can produce lactate under anaerobic conditions but tissues with active glycolysis produce excess lactate from glucose under normal conditions and this lactate tends to spill over into the blood. Lactate is produced from pyruvate in a reaction catalysed by lactate dehydrogenase:

Pyruvate + NADH + H+ <=> Lactate + NAD+

 

At rest, the tissues which normally produce excess lactate are:
    * skin - 25% of production
    * red cells - 20%
    * brain - 20%
    * muscle - 25%
    * gut - 10%

 

During heavy exercise, the skeletal muscles contribute most of the much increased circulating lactate.
During pregnancy, the placenta is an important producer of lactate which passes into both the maternal and the foetal circulations.

 

Metabolism of lactate

 

Lactate is metabolised predominantly in the liver (60%) and kidney (30%). Half is converted to glucose (gluconeogenesis) and half is further metabolised to CO2 and water in the citric acid cycle. The result is no net production of H+ (or of the lactate anion) for excretion from the body. Other tissues can use lactate as a substrate and oxidise it to CO2 and water but it is only the liver and kidney that have the enzymes that can convert lactate to glucose.

 

# The renal threshold for lactate is about 5 to 6 mmols/l so at normal plasma levels, no lactate is excreted into the urine.

# The small amount of lactate that is filtered (180mmol/day) is fully reabsorbed.

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Lactic acidosis can occur due to:
    * excessive tissue lactate production
    * impaired hepatic metabolism of lactate

 

 

In situations where lactic acidosis is clearly due to excessive production alone (such as severe exercise or convulsions), the acidosis usually resolves (due to hepatic metabolism) within about an hour once the precipitating disorder is no longer present. In severe exercise, lactate levels can rise to very high levels eg up to 30 mmol/l. Respiratory compensation for the acidosis may not be significant because of the short time involved. However, there are other causes of hyperventilation present and arterial pCO2 is typically reduced providing partial compensation. For example, exercise results in markedly increased ventilation and the cause of this is largely unknown. The arterial pCO2 usually falls with exercise and this is not considered to be due to the lactic acidosis as it occurs even in less severe exercise where there is little excess lactate produced.

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Hyperlactaemia: a level from 2 mmols/l to 5 mmol/l.

Severe Lactic Acidosis: when levels are greater than 5 mmols/l

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Lactic acidosis is commonly classified into either Type A or Type B (Cohen & Woods, 1976) with the main differentiating point being the adequacy of tissue oxygen delivery. In both types, the fundamental problem is the inability of the mitochondria to deal with the amount of pyruvate with which they are presented.

 

Type A lactic acidosis refers to circumstances where the clinical assessment is that tissue oxygen delivery is inadequate. This is the most common clinical situation.

If hypoxaemia is the only factor present, it needs to be severe (eg paO2 < 35mmHg) to precipitate lactic acidosis because of the protection afforded by the body’s compensatory mechanisms which increase tissue blood flow. Similarly anaemia needs to be severe (eg [Hb] <5G%)

 

Reduced perfusion is the most important factor in causing impaired oxygen delivery in type A lactic acidosis.
 
Anaemia or hypoxaemia alone is not sufficient unless severe or associated with reduced perfusion.

 

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Type B lactic acidosis refers to situations in which there is no clinical evidence of reduction in tissue oxygen delivery. Carbohydrate metabolism is disordered for some reason and excess lactic acid is formed. Research using more sophisticated methods to assess tissue perfusion have now shown that occult tissue hypoperfusion is present in many cases of Type B acidosis.
An ischaemic bowel can produce large amounts of lactate. Mesenteric ischaemia can cause a severe lactic acidosis even if perfusion in the rest of the body is adequate. This situation can easily be overlooked especially in those cases where abdominal clinical signs are minimal.

 

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Any factor which stimulates glycolysis (eg catecholamine administration, cocaine) will lead to an increased lactate production. Lactic acidosis occurs in up to 10% of patients presenting with diabetic ketoacidosis. This may be due to poor peripheral perfusion or phenformin administration but may occur without the presence of these factors.

 

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Classification of Some Causes of Lactic Acidosis (Cohen & Woods, 1976)
Type A Lactic Acidosis : Clinical Evidence of Inadequate Tissue Oxygen Delivery
    *
      Anaerobic muscular activity (eg sprinting, generalised convulsions)
    *
      Tissue hypoperfusion (eg shock -septic, cardiogenic or hypovolaemic; hypotension; cardiac arrest; acute heart failure; regional hypoperfusion esp mesenteric ischaemia)
    *
      Reduced tissue oxygen delivery or utilisation (eg hypoxaemia, carbon monoxide poisoning, severe anaemia)
Type B Lactic Acidosis: No Clinical Evidence of Inadequate Tissue Oxygen Delivery
    *
      type B1 : Associated with underlying diseases (eg ketoacidosis, leukaemia, lymphoma, AIDS)
    *
      type B2: Assoc with drugs & toxins (eg phenformin, cyanide, beta-agonists, methanol, nitroprusside infusion, ethanol intoxication in chronic alcoholics, anti-retroviral drugs)
    *
      type B3: Assoc with inborn errors of metabolism (eg congenital forms of lactic acidosis with various enzyme defects eg pyruvate dehydrogenase deficiency)
Note: This list does not include all causes of lactic acidosis

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The basic investigations needed to supplement the history, examination and electrolyte results in differentiating the causes of a high anion gap acidosis are:
    * blood glucose level
    * urinary ketones
    * urea & creatinine
    * urine output
    * blood lactate level
    * calculation of osmolar gap

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The principles of management of patients with lactic acidosis are:
    * Diagnose and correct the underlying condition (if possible)
    * Restore adequate tissue oxygen delivery (esp restore adequate perfusion)
    * Avoid sodium bicarbonate (except possibly for treatment of associated severe hyperkalaemia)

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