Pφ

Two toxic alcohol ingestions that lead to a severe anion-gap acidosis are methanol and ethylene glycol. The low molecular weight of these substances allows for entry into cells. Methanol and ethylene glycol are metabolized to formic acid and glycolic acid, respectively, and this metabolism generates H+ ions, resulting in a high–anion gap acidosis. These substances are found in automotive antifreeze and de-icing solutions, windshield wiper fluid, solvents, and cleaners, and are ingested accidentally or as a suicide attempt.

TP

Patients with methanol ingestion present with GI symptoms (abdominal pain, vomiting), central nervous system (CNS) symptoms (inebriation, headache, lethargy, coma), and an anion gap metabolic acidosis usually 12–24 hours after ingestion. No alcoholic fetor is present. An additional clue to the diagnosis of methanol ingestion is the presence of visual disturbances, as formic acid causes retinal injury. Ethylene glycol is found in antifreeze, and its ingestion has a similar clinical presentation but does not produce visual disturbances. The toxic metabolite of ethylene glycol causes kidney damage, and these patients often present with renal failure. Ethylene glycol, in addition to being metabolized to glycolic acid, is metabolized to oxalate, causing precipitation of calcium oxalate crystals, which can cause flank pain and further deterioration in renal function. Calcium oxalate crystals can be detected in the urine and may be seen in the form of calcium oxalate dihydrate (envelope-shaped crystals) or, more commonly, calcium oxalate monohydrate (needle-shaped or dumbbell-shaped crystals). Additionally, the urine will be fluorescent under a Wood lamp.

Dx

Recognition of these ingestions should be made early, as prompt therapy is associated with significant decrease in morbidity and mortality. An increased osmolar gap is an early clue to diagnosis. The osmolar gap is defined as the difference between the measured serum osmolality and the calculated osmolality. An osmolar gap >15 mOsm/kg indicates that a toxic ingestion is the likely diagnosis. Of note, an osmolar gap can also be present in other conditions that are not associated with a high–anion gap metabolic acidosis, such as ethanol or isopropyl alcohol ingestion. Ethylene glycol poisoning can also cause hypocalcemia.

Pφ

Lactic acidosis is a frequent cause of increased anion gap in hospitalized patients. Lactate is the end product of anaerobic metabolism of glucose, and, under normal conditions, its production is minimal. When lactate production increases faster than lactate can be metabolized, lactic acidosis ensues. Lactic acid exists in two forms, called isomers: L-lactate and D-lactate. L-lactate is produced in human metabolism and increases with impairments in tissue oxygenation secondary to increased anaerobic metabolism. D-lactate is produced by bacteria and is therefore primarily seen in patients with colonic bacterial overgrowth such as those with short-gut syndrome, gastric bypass, or small bowel resection.

TP

Patients with lactic acidosis can present with abdominal pain, nausea, vomiting, CNS symptoms, and alterations in respiration. The severity of symptoms varies with the cause and degree of acidosis. L-lactic acidosis can be classified as type A or type B lactic acidosis. Type A lactic acidosis occurs in the setting of tissue hypoperfusion and is usually seen in shock, cardiopulmonary arrest, and/or hypoxemia. A transient lactic acidosis may be seen with seizures or excessive exercise. Type B lactic acidosis is found in patients without symptoms of hypoperfusion and often results from medications that interfere with lactate or pyruvate metabolism, such as metformin or reverse transcriptase inhibitors.

Dx

The diagnosis of lactic acidosis should be considered in all cases of anion gap metabolic acidosis. In lactic acidosis, the anion lactate accounts for the increase in anion gap. Lactic acidosis is diagnosed when elevated levels of serum lactate are demonstrated. Routine serum lactate assays measure the L-lactate isomer but do not detect the D-lactate isomer. If D-lactic acidosis is suspected, the appropriate assay should be ordered.

Pφ

Ketones are produced when the body metabolizes adipose tissue for energy and the liberated fatty acids are metabolized to ketoacids (β-hydroxybutyric and acetoacetic acid), which can be detected in serum and urine. The two most common types of ketoacidosis are diabetic ketoacidosis (DKA) and alcoholic ketoacidosis (AKA). In both situations a decrease in the insulin-to-glucagon ratio leads to fatty acid mobilization and ketoacid accumulation.

TP

Patients with DKA typically present with hyperglycemia, polyuria, polydipsia, nausea, vomiting, abdominal pain, and hyperventilation. Physical exam may reveal signs of volume depletion resulting from a combination of an osmotic diuresis from hyperglycemia along with vomiting and poor oral intake. Fruity odor and hyperventilation may also be noted.

AKA should be suspected in a patient with a history of alcohol abuse with recent binge drinking and poor oral intake. These patients, in contrast to those with DKA, may be hypoglycemic on presentation.

Dx

The diagnosis of DKA is made in a hyperglycemic patient with a high–anion gap acidosis and detection of serum or urine ketones. AKA is diagnosed in a patient with a history of alcohol abuse and high–anion gap acidosis with positive serum or urine ketones. The predominant ketone in AKA is β-hydroxybutyrate.

Pφ

Early in the course of renal failure, a non–anion gap, hyperchloremic metabolic acidosis may be present due to impaired ammonium excretion. However, as the GFR decreases further, the kidney becomes unable to excrete organic and inorganic anions, causing a high–anion gap metabolic acidosis.

TP

Patients generally present with symptoms secondary to renal failure and the resulting metabolic acidosis. These symptoms include anorexia, nausea, vomiting, hyperventilation, congestive heart failure, muscle weakness, and changes in mental status.

Dx

The presence of an elevated BUN and creatinine with acidosis suggests that renal failure is the cause of metabolic acidosis.

Pφ

Salicylate (aspirin) intoxication is another cause of elevated anion gap metabolic acidosis. At toxic concentrations, salicylate uncouples oxidative phosphorylation and leads to increased production of organic acids. Aspirin is widely available, and therefore salicylate intoxication is a common poisoning.

TP

The symptoms of salicylate intoxication are dose-dependent, with most patients showing signs of toxicity at plasma concentrations >40–50 mg/dL. Common clinical manifestations include nausea, vomiting, tinnitus, pulmonary edema, altered mental status, and coma. Adults may present with a mixed disorder of high–anion gap acidosis with respiratory alkalosis, as salicylate stimulates the respiratory center, causing increased ventilation. Severe intoxication can lead to death from CNS toxicity and cardiorespiratory depression.

Dx

The diagnosis is made in the setting of an increased anion gap acidosis in combination with a respiratory alkalosis in a patient with an elevated plasma salicylate concentration.

Pφ

Intestinal fluid distal to the stomach has a high concentration of HCO3, and GI HCO3 loss is a common cause of metabolic acidosis. The HCO3 loss most commonly occurs with diarrhea but can also be seen with excessive biliary and/or pancreatic fluid loss. The excessive volume loss causes the kidneys to reabsorb NaCl, resulting in a normal anion gap hyperchloremic acidosis. The kidneys, in response to acidosis, will increase urinary excretion of NH4+, which will lead to a negative urine anion gap.

TP

Patients typically present with a history of diarrhea and serum chemistries showing both a normal anion gap acidosis and hypokalemia. With excessive volume loss, they can present with hypotension and tachycardia.

Dx

The diagnosis of GI HCO3 loss as the etiology of metabolic acidosis is made by detection of a normal anion gap metabolic acidosis with a negative urine anion gap and a clinical history suggestive of GI HCO3 loss.

Pφ

RTA refers to a group of disorders characterized by hyperchloremic, normal anion gap metabolic acidosis as a result of impaired renal HCO3 absorption or H+ secretion in the setting of a normal GFR. RTA may be a primary disorder or secondary to a number of systemic diseases such as diabetes mellitus, multiple myeloma, or autoimmune diseases. Medications and toxins have also been known to cause RTA.

TP

Patients are generally asymptomatic but may present with nonspecific symptoms related to the underlying cause of RTA. Patients with type I RTA often develop nephrolithiasis. Patients with type IV RTA are often hyperkalemic. However, often RTA may be incidentally discovered on routine blood screening.

Dx

RTA is suspected in the presence of a normal anion gap, hyperchloremic metabolic acidosis in conjunction with a positive urine anion gap. This indicates an inability of the kidney to excrete NH4.

Pφ

Contraction alkalosis is a term used to describe a combined presentation of volume contraction and primary metabolic alkalosis. It is seen in patients with vomiting and diuretic use and results from the loss of HCO3-free fluid. The alkalosis is then maintained by chloride depletion. Specific cells in the distal tubule exchange chloride for HCO3, and thus chloride depletion will not allow HCO3 excretion and correction of the alkalosis.

TP

Metabolic alkalosis is generally well tolerated and is only discovered on routine laboratory testing. However, patients with serum HCO3 concentrations > 50 mmol/L may manifest with neurologic symptoms such as seizures, delirium, or stupor. Other symptoms may be related to other associated abnormalities such as hypokalemia and volume depletion.

Dx

The diagnosis requires a history suggesting volume depletion and Cl− loss such as vomiting, nasogastric suctioning, and/or diuretic use. Laboratory data reveal increased serum HCO3, hypokalemia, and an elevated arterial pH. Urine electrolytes show a urine Cl− < 20 mmol/L.

Pφ

Milk-alkali syndrome is characterized by metabolic alkalosis, hypercalcemia, and renal insufficiency. It occurs in the setting of continuous alkali (sodium bicarbonate) ingestion along with excess calcium intake (milk or CaCO3). The hypercalcemia produces a reduction in GFR. This reduction in GFR does not allow the kidneys to excrete HCO3, and metabolic alkalosis develops.

TP

Approximately 50% of these patients are asymptomatic. The remaining 50% present with symptomatic hypercalcemia, including nausea, vomiting, weakness, muscle aches, polyuria, polydipsia, nephrolithiasis, and mental status changes.

Dx

A history of calcium and alkali ingestion (often in the form of calcium carbonate), along with laboratory data indicating hypercalcemia and metabolic alkalosis, suggests milk-alkali syndrome.