Clinically, increased blood lactate occurs as a consequence of overproduction or decreased clearance (underutilization).

Overproduction:

Living cells utilize energy that comes principally from glucose metabolism.  In the first step, glycolysis, glucose is metabolized into pyruvate, yielding a net of 2 ATP molecules:

Glucose (C₆H₁₂O₆) + 2 ATP + 2 NAD⁺ --> 2 pyruvate + 4 ATP + 2 NADH

During aerobic respiration, pyruvate enters the citric acid (Krebs) cycle to produce more ATP and NADH:

2 acetyl-CoA + 2 oxaloacetate --> 4 CO₂ + 6 NADH + 2 FADH₂ + 2 ATP + 2 oxaloacetate.  

Under conditions of aerobic respiration, the NADH molecules generated by glycolysis and the citric acid cycle undergo oxidative phosphorylation in the mitochondria, yielding a large quantity of ATP:

10 NADH + 2 FADH₂ --> 34 ATP.


Net production of L-lactic acid (the principle isoform of lactic acid generated be mammalian cells) occurs then when the body must regenerate ATP without oxygen. The bottom line is that 1 H⁺ is produced per ATP regenerated from glucose. Quantitatively, because a patient at rest needs to regenerate 72 mmol of ATP per minute, as much as 72 mmol of H+ can be generated per minute during anoxia.

2 ATP --> 2(ADP + P_i) + biologic work
Glucose + 2(ADP +P_i) --> 2H⁺ + L-lacatate^- + 2 ATP

Increased lactate production may occur as a result of diminished oxygen supply to cells, which then rely on anaerobic metabolism. This may occur in circulatory shock, or in cases of reduced oxygen utilization (for example, cyanide toxicity). In this patient, the blood pressure was well preserved, so shock is an unlikely explanation. Impaired hepatic clearance of lactate due to hepatic failure is a likely explanation for the observed hyperlactatemia in the setting of severely abnormal liver function.

Underutilzation:

There are two major ways to remove L-lactic acid: oxidation or conversion to glucose.

To oxidize 1 mmol of lactate, 3 mmol of oxygen must be consumed (18 mmol of ATP must be formed). If all organs were “persuaded” to oxidize L-lactate to yield 100% of their ATP requirements, only 4 mmol of L-lactate could be oxidized per minutes at rest (because 72 mmol of ATP are used per minute).   

L-lacatate^- + H⁺ + 3O₂ + 3(ADP + P_i) --> 8 ATP + 3CO₂ + 3H₂O

The other major metabolic way in which to remove lactate is via gluconeogenesis. In conditions of low cellular oxygen, pyruvate cannot undergo aerobic metabolism, and instead may undego anerobic metabolism, resulting in the conversion of pyruvate to lactic acid, which is rapidly buffered in the blood by bicarbonate into lactate. Lactate then undergoes conversion back into pyruvate via the Cori cycle in the liver and, to a smaller extent, kidney [1]. Hepatic and renal insufficiency may contribute to lactic acidosis, and given evidence of acute hepatic failure, the lactic acidosis present may be attributable to hepatic failure. However, there is no evidence of renal insufficiency in this case, so renal failure in unlikely to be the cause.

Lactate accumulates when there is excess pyruvate production, during preferential conversion of pyruvate into lactate (instead of pyruvate entering the citric acid cycle) or reduced conversion of pyruvate to CO₂ and water. The maximum rate of gluconeogenesis is 4 mmol/min. Its important to note that for this reason, lactate accumulation occurs rapidly and clearance is much slower.

Biguanide drugs (phenformin, metformin) may result in lactic acidosis, though the mechanisms are poorly understood, including increased intestinal production of lactate, decreased hepatic metabolism of lactate, and altered hepatocyte glucose metabolism [2]. Lactic acidosis in patients taking metformin is usually mild (< 2 mEq/L) and risk factors include renal failure and congestive heart failure. Although this patient was reported to have diabetes mellitus, type 2, there is no report of his taking metformin, so metformin-associate d lactic acidosis is an unlikely explanation.

Lactic acidosis has been reported to be a complication of hematologic malignancies, especially when there is hepatic involvement [3]. The mechanisms are uncertain, but may include increased metabolism by the malignant cells or impaired hepatic metabolism of lactate due to replacement of hepatic parenchyma by metastatic disease. Since this patient had a high tumor burden and metastasis to the liver, lymphoma probably contributed to the observed hyperlactatemia.