Increased anion gap metabolic acidoses

The major causes of increased anion gap acidosis are lactic acidosis, ketoacidosis, uremia, salicylate overdose, and poisoning by methanol, ethylene glycol, and other toxins. Lactic acidosis is an important cause of increased anion gap acidosis in the critically ill. The pathway of lactate metabolism is shown in Fig 2.. Under normal conditions, lactate is produced by a variety of tissues and is metabolized in the liver and kidneys, where it may be converted back to glucose. Hyperlactatemia occurs if lactate production exceeds excretion. Hyperlactatemia in the presence of acidemia defines lactic acidosis.

Fig. 2 Metabolism of lactate. Increased glycolysis or accumulation of pyruvate or cytosolic NADH favors metabolism of pyruvate to lactate, particularly if pyruvate cannot be metabolized in the mitochondrion, as in anaerobic conditions. Cytosolic NAD + is regenerated by transportation of malate and glycerol-3-phosphate to the mitochondrion, where they are oxidized through the respiratory chain. Anaerobic metabolism of 1 mol of glucose to lactate yields only 2 mol of ATP, whereas aerobic metabolism produces 38 mol of ATP. H+ is produced by hydrolysis of ATP. (LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; TCA cycle, tricarboxylic acid cycle.)

Lactic acidosis is caused by hypoxic and non-hypoxic mechanisms ( Table..,2.) (iârD®ti..ând Schmjdtiin!992.; .E.m..m.e.tt.e.La.L 1.992.; .S.c.h.mi.d.L.19.9.2; Siacpoole.,1993). During tissue hypoxia, the ratio of NADH to NAD + (redox ratio) rises and/or pyruvate levels increase, so that conversion of pyruvate to lactate is stimulated and lactate accumulates (see Fig.2). Anaerobic glycolysis increases pyruvate because it is the only mechanism of energy production during hypoxia.

Table 2 Hypoxic and non-hypoxic mechanisms of lactic acidosis

Tissue hypoxia can be classified as stagnant (low flow), anemic, or hypoxic hypoxia. Global tissue hypoxia due to circulatory shock is the most common etiology of hypoxic hyperlactatemia in the intensive care unit (ICU). In addition, it is important to consider regional hypoperfusion, particularly of the gastrointestinal tract, and severe exertion (including acute severe asthma, heat stroke, and seizures) as causes of hyperlactatemia. Uncoupling of oxidative phosphorylation is also important and may occur with salicylate, cyanide (a product of nitroprusside metabolism), methanol, isoniazid, and carbon monoxide (CO) intoxication. Rarely, hyperlactatemia is caused by severe anemia, malignancies, and CO poisoning.

There are several potential non-hypoxic mechanisms of lactic acidosis (T,ab.l.e..2) in critically ill patients. Hyperlactatemia can also be caused by decreased metabolism by liver and kidney. Therefore mild hyperlactatemia can occur in patients who have hepatic failure, cirrhosis, or renal failure. Non-hypoxic lactic acidosis is a more important mechanism in the ICU than is generally appreciated.

The primary pathophysiological abnormality of ketoacidosis is low insulin concentration and high levels of counter-regulatory hormones. In the absence of insulin, fatty acids are oxidized in the liver to ketoacids, primarily acetoacetate and b-hydroxybutyrate. This response is normal in the fasting state. Thus starvation induces modest ketoacidosis which is self-limiting. Diabetic ketoacidosis is caused by severe insulinopenia and hyperglucagonemia. Furthermore, ketoacidosis is exacerbated by associated volume depletion.

Alcoholic ketoacidosis can be serious and is due to the combined effects of starvation (as described above) and alcohol withdrawal (which induces a marked elevation of counter-regulatory hormones). Alcoholic ketoacidosis is frequently accompanied by hypoglycemia and lactic acidosis (due to volume depletion and ethanol-induced alteration in the redox ratio).

Renal failure initially reduces ammoniagenesis, which may cause a hyperchloremic normal anion gap acidosis. The increased anion gap acidosis of renal failure is caused by accumulation of unmeasured anions, such as phosphate and sulfate, but particularly the anions of non-volatile endogenous organic acids (such as peptides and amino acid derivatives). There is concomitant reduction in HCO 3- owing to buffering in the face of diminished HCO3- reclamation and regeneration. In chronic renal failure, HCO3- is stabilized by the enormous buffering capacity of bone ( Emmett ef a/ 1992; S..c,hMdL1992.).

Poisoning with salicylate causes complex acid-base disturbances (Barnettand Schmidt 1992; .E.m..m..e.tt.e.t.,a.!; 1992). Salicylate itself is an organic acid, but it also stimulates respiratory centers, resulting in hyperventilation and respiratory alkalosis. The latter induces glycolysis, further accelerated by hypoglycemia (due to salicylate-stimulated insulin secretion). There are several causes of increased anion gap acidosis in salicylate poisoning. Salicylate uncouples oxidative phosphorylation, thus inhibiting normal aerobic metabolism and causing a mild lactic acidosis. In addition, ketoacidosis may develop. Thus the increased anion gap of salicylate poisoning is caused by accumulation of salicylate, lactate, ketoacids, and other organic acids.

The toxicity of alcohol intoxications is related to accumulation of their metabolites (iB.arD.§.tLiQd S.9h.m..idi.1.992.; .E..m,m.§.ti..§t,§L 1992.; Schmidt.1992). Metabolism of methanol produces formaldehyde and formic acid, which causes an increased anion gap acidosis. Formate also inhibits cytochrome oxidase and induces lactic acidosis. Ethylene glycol is oxidized to glycolic and oxalic acids.

Paraldehyde is a rare cause of increased anion gap acidosis. It is metabolized to acetaldehyde and subsequently acetic acid, but this does not seem to account for the acidosis (EmmettefaA 1992).

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