Normochloremic metabolic acidosis generally results from addition of organic acids such as lactate, acetoacetate, beta-hydroxybutyrate, and exogenous toxins. Other anions such as isocitrate, alpha-ketoglutarate, malate, and D-lactate may contribute to the anion gap of lactic acidosis, DKA, and acidosis of unknown etiology. Uremia causes an increased anion gap metabolic acidosis from unexcreted organic acids and anions.
Lactic acidosis is a common cause of metabolic acidosis, producing an elevated anion gap and decreased serum pH when present without other acid-base disturbances. Lactate is formed from pyruvate in anaerobic glycolysis. Normally, lactate levels remain low (1 mEq/L) because of metabolism of lactate principally by the liver through gluconeogenesis or oxidation via the Krebs cycle.
In lactic acidosis, lactate levels are at least 4–5 mEq/L but commonly 10–30 mEq/L. There are two basic types of lactic acidosis.
Type A (hypoxic) lactic acidosis is more common, resulting from decreased tissue perfusion; cardiogenic, septic, or hemorrhagic shock; and carbon monoxide or cyanide poisoning. These conditions increase peripheral lactic acid production and decrease hepatic metabolism of lactate as liver perfusion declines.
Type B lactic acidosis may be due to metabolic causes (eg, diabetes, ketoacidosis, liver disease, kidney disease, infection, leukemia, or lymphoma) or toxins (eg, ethanol, methanol, salicylates, isoniazid, or metformin). Propylene glycol can cause lactic acidosis from decreased liver metabolism; it is used as a vehicle for intravenous drugs, such as nitroglycerin, etomidate, and diazepam. Parenteral nutrition without thiamine causes severe refractory lactic acidosis from deranged pyruvate metabolism. Patients with short bowel syndrome may develop d-lactic acidosis with encephalopathy due to carbohydrate malabsorption and subsequent fermentation by colonic bacteria. Nucleoside analog reverse transcriptase inhibitors can cause type B lactic acidosis due to mitochondrial toxicity.
Idiopathic lactic acidosis, usually in debilitated patients, has an extremely high mortality rate. (For treatment of lactic acidosis, see below and Chapter 27-05.)
B. Diabetic Ketoacidosis (DKA)
DKA is characterized by hyperglycemia and metabolic acidosis with an increased anion gap:
where B– is beta-hydroxybutyrate or acetoacetate, the ketones responsible for the increased anion gap. The anion gap should be calculated from the measured serum electrolytes; correction of the serum sodium for the dilutional effect of hyperglycemia will exaggerate the anion gap. Diabetics with ketoacidosis may have lactic acidosis from tissue hypoperfusion and increased anaerobic metabolism.
During the recovery phase of DKA, a hyperchloremic non-anion gap acidosis can develop because saline resuscitation results in chloride retention, restoration of GFR, and ketoaciduria. Ketone salts (NaB) are formed as bicarbonate is consumed:
The kidney reabsorbs ketone anions poorly but can compensate for the loss of anions by increasing the reabsorption of Cl–.
Patients with DKA and normal kidney function may have marked ketonuria and severe metabolic acidosis but only a mildly increased anion gap. Thus, the size of the anion gap correlates poorly with the severity of the DKA; the urinary loss of Na+ or K+ salts of beta-hydroxybutyrate will lower the anion gap without altering the H+ excretion or the severity of the acidosis. Urine dipsticks for ketones test primarily for acetoacetate and, to a lesser degree, acetone but not the predominant ketoacid, beta-hydroxybutyrate. Dipstick tests for ketones may become more positive even as the patient improves due to the metabolism of beta-hydroxybutyrate. Thus, the patient’s clinical status and pH are better markers of improvement than the anion gap or ketone levels.
C. Alcoholic Ketoacidosis
Chronically malnourished patients who consume large quantities of alcohol daily may develop alcoholic ketoacidosis. Most of these patients have mixed acid-base disorders (10% have a triple acid-base disorder). Although decreased HCO3– is usual, 50% of the patients may have normal or alkalemic pH. Three types of metabolic acidosis are seen in alcoholic ketoacidosis: (1) Ketoacidosis is due to beta-hydroxybutyrate and acetoacetate excess. (2) Lactic acidosis: Alcohol metabolism increases the NADH:NAD ratio, causing increased production and decreased utilization of lactate. Accompanying thiamine deficiency, which inhibits pyruvate carboxylase, further enhances lactic acid production in many cases. Moderate to severe elevations of lactate (greater than 6 mmol/L) are seen with concomitant disorders such as sepsis, pancreatitis, or hypoglycemia. (3) Hyperchloremic acidosis from bicarbonate loss in the urine is associated with ketonuria (see above). Metabolic alkalosis occurs from volume contraction and vomiting. Respiratory alkalosis results from alcohol withdrawal, pain, or associated disorders such as sepsis or liver disease. Half of the patients have hypoglycemia or hyperglycemia. When serum glucose levels are greater than 250 mg/dL (13.88 mmol/L), the distinction from DKA is difficult. The absence of a diabetic history and normoglycemia after initial therapy support the diagnosis of alcoholic ketoacidosis.
(See also Chapter 38-14.) Multiple toxins and drugs increase the anion gap by increasing endogenous acid production. Common examples include methanol (metabolized to formic acid), ethylene glycol (glycolic and oxalic acid), and salicylates (salicylic acid and lactic acid). The latter can cause a mixed disorder of metabolic acidosis with respiratory alkalosis. In toluene poisoning, the metabolite hippurate is rapidly excreted by the kidney and may present as a normal anion gap acidosis. Isopropanol, which is metabolized to acetone, increases the osmolar gap, but not the anion gap. If there is a concern for toxin ingestion, the Poison Control Center should be contacted immediately; in the United States, the center is available 24 hours at 1-800-222-1222.
As the GFR drops below 15–30 mL/min, the kidneys are increasingly unable to synthesize NH3. The reduced excretion of H+ and organic acids (eg, phosphate and sulfate) as NH4Cl results in an increased anion gap metabolic acidosis.