Lactic acidosis is the most common metabolic acidosis. It occurs in association with a wide variety of underlying processes and may represent a well-tolerated, physiologic event or a life-threatening, pathologic condition. Lactic acidosis is classified based upon oxygen supply to the tissues. Type A is that clearly associated with clinically evident hypoperfusion or hypoxia, and type B includes all other forms, those in which there is no evidence of tissue anoxia. Lactic acidosis is often diagnosed during the evaluation of an anion gap acidosis. Treatment is directed toward identification and correction of the underlying disorder and restitution of normal acid-base equilibrium.

PATHOPHYSIOLOGY

Lactate

Lactate is a metabolic product of anaerobic glycolysis and under normal conditions is in equilibrium with its immediate precursor, pyruvate. The basal production of lactate in a 70-kg person is approximately 1300 mEq/day, and the normal lactate concentration in extracellular fluid is about 1 mEq/L. The maintenance of lactate homeostasis is a complex, dynamic process involving interorgan balance between lactate production and utilization. Virtually all body tissues are capable of producing lactate, but skeletal muscle, erythrocytes, brain, skin, and intestinal mucosa are the most active. The utilization of lactate takes place in the liver and kidneys and to a lesser extent in the heart and skeletal muscle. Lactate is primarily disposed of in the liver and kidneys via gluconeogenesis, a process that requires the conversion of lactate back to pyruvate.
Lactate is formed from pyruvate as an end product of anaerobic glycolysis. This oxidation-reduction reaction requires reduced nicotinamide adenine dinucleotide (NADH) and hydrogen ion (H+) and is catalyzed by lactate dehydrogenase (LDH).
The equilibrium of this reaction strongly favors the formation of lactate. The normal ratio of lactate to pyruvate is 10:1. Lactate is a metabolic blind end; it cannot be utilized in any other intracellular reactions and must be converted back to pyruvate for gluconeogenesis or oxidation to CO2 and H2O via the Krebs cycle. The result of this biochemical reaction is to produce energy in the form of adenosine triphosphate (ATP) and to oxidize NADH to NAD. A small amount of lactic acid is produced even at rest and under aerobic conditions. In the presence of oxygen and essential cofactors, lactate is converted back to pyruvate; it does not accumulate and maintains equilibrium with pyruvate.
A variety of factors may alter this normal process. The concentration of lactate in the cytosol depends primarily upon the concentration of pyruvate, the intracellular redox state (NADH/NAD), and the intracellular pH. The net effect of these multiple factors determines the intracellular concentration of lactate.

Pyruvate

Since lactate can be eliminated only by conversion back to pyruvate, lactate concentration is intimately interrelated to the fate of pyruvate. Pyruvate is a key intermediary at the junction of several important pathways. The major sources of pyruvate are glycolysis, in which pyruvate is formed from the oxidation of glucose, and transamination, a process by which pyruvate can be derived from amino acids, especially alanine. Pyruvate may be utilized via gluconeogenesis in which pyruvate is a substrate in the formation of glucose, and mitochondrial oxidation, in which pyruvate enters the mitochondria for oxidation to CO2 and H2O. A variety of factors may alter these normal pathways. For example, rapid glycolysis can be induced by alkalosis, protein catabolic states may increase transamination, metabolic poisons may impair mitochondrial function, or key enzymes and cofactors may be inactivated or unavailable. The concentration of pyruvate, and thus the concentration of lactate, depends upon the net production and consumption of pyruvate by these various routes.

Redox State

The intracellular redox state is a critical factor in determining the concentration of lactate. The availability of oxygen at the tissue level is an important determinant of the cellular redox. During prolonged anaerobic conditions, lactate cannot be reoxidized back to pyruvate because of a lack of NAD. Normally, NADH can be reoxidized to NAD within the mitochondria via the electron transport chain coupled with oxidative phosphorylation. Electron transport abruptly ceases during anoxia. NAD is not available for lactate conversion, and lactate accumulates. This mechanism is thought to be operative during type A lactic acidosis. Other factors may alter the cellular redox, and consequently, alterations in the NADH/NAD ratio do not solely reflect tissue oxygenation.

Intracellular pH

A third major determinant of lactate concentration within the cytosol is the intracellular hydrogen ion concentration. Changes in the intracellular pH affect enzymatic reactions, lactate transport, and the lactate/pyruvate ratio. Some of these effects may counterbalance each other. In general, a fall in pH causes decreased lactate production, whereas an increase in pH causes increased lactate concentration. One important aspect of a change in intracellular pH is its effect on the liver. As the pH declines, lactate uptake by the liver decreases. Additionally, when the pH is 7.0 or less, the liver becomes an organ of lactate production instead of lactate clearance.

Lactate Utilization

The liver and kidneys are the major organs that consume lactate. Gluconeogenesis is the main pathway utilized by these organs in lactate removal. This process utilizes the hydrogen ions produced during the formation of lactic acid and this acts to maintain acid-base balance. The liver normally clears more than half the total daily lactate load, and the kidneys remove approximately 30 percent. Some researchers believe that the kidneys have a negligible role in lactate clearance and that other extrahepatic sites are more important. Of the approximately 1300 mEq of lactate produced each day, 60 to 70 mEq of lactate is extracted by the liver every 2 h. The hydrogen ion that is consumed by the liver during this period is roughly equivalent to the total amount of hydrogen ion excreted daily by the kidneys. By virtue of the liver's ability to clear lactate, the role of the liver in the maintenance of the overall acid-base balance is very important. In addition, the liver has a large reserve capacity to extract lactate; this has been estimated to be as high as 3400 to 4000 mEq/day. Obviously, any situation which converts the liver from a lactate-consuming to a lactate-producing organ results in serious acid-base disturbance. Lactic acid clearance by the liver may be reduced with decreased hepatic blood flow or parenchymal hypoxia.
The kidneys carry out their role in lactate clearance primarily through gluconeogenesis, not excretion. The renal threshold for lactate is about 7 to 10 mEq/L, so the amount of lactate excreted by the kidneys at normal plasma levels is negligible. The kidneys may also dispose of lactate through oxidation, but this is not the preferred pathway. At a pH of less than 7.1, lactate uptake by the kidneys may be decreased, and at a pH of 7.0 or below, the kidneys like the liver may produce lactic acid.
Skeletal and cardiac muscle is capable of extracting some lactate from the circulation. The relative role of these sites of lactate clearance is not clear. Lactate utilization by skeletal muscle may depend on the concentration of lactate and whether the muscle is active or at rest.

Lactic Acidosis

Lactic acidosis can be thought of as an imbalance between the rate of production of lactate by tissues active in glycolysis and the rate of utilization by tissues active in gluconeogenesis. Disagreement exists over whether the primary mechanism responsible for lactic acidosis is overproduction or underutilization.
Lactic acid is a strong organic acid that is almost completely dissociated at physiologic pH. The ratio of lactate ion to undissociated lactic acid at a pH of 7.4 is more than 3000:1. For each milliequivalent of lactic acid produced, equal amounts of hydrogen ion and lactate are liberated. Hydrogen ions are initially buffered by bicarbonate and other buffers and then consumed during the utilization of lactate via gluconeogenesis or oxidation. Acid-base balance is therefore maintained. Under circumstances of increased lactic acid production and/or decreased lactic acid utilization, body buffers are saturated by the excess hydrogen ions. When this is of sufficient magnitude, acidosis results. Whether the resultant lactic acidosis is clinically significant depends upon the underlying process responsible for the lactic acid accumulation and the preexistent acid-base status.

Diagnosis

Lactic acidosis is a metabolic acidosis caused by the accumulation of lactate and hydrogen ion. It is accompanied by an elevated blood lactate concentration, but there is no consensus on what level of lactate defines lactic acidosis. The normal plasma lactate level is 0.5 to 1.5 mEq/L. In general, a lactate concentration of 5 to 6 mEq/L is considered indicative of significant acid-base disturbance. Some authors have included demonstration of a reduced arterial pH, <=7.35, as a criterion for diagnosis. However, if there is a coexistent alkalosis, the pH could be normal or even alkalemic in the face of significant lactic acidosis.
The presence of hyperlactemia per se does not mean that the patient has clinically significant lactic acidosis. Many situations encountered clinically may result in elevation of blood lactate levels but not produce significant clinical consequences. Exercise; hyperventilation; infusions of glucose, saline, or bicarbonate; and injections of insulin or epinephrine may all cause elevation of lactate levels without clinical manifestations. Plasma lactate concentrations after vigorous exercise or maximum work have been reported to reach 14 to 30 mEq/L. In patients with grand mal seizures, levels of 12.7 mEq/L have been recorded. In spite of these high levels, the lactate production is self-limited, and the lactate is rapidly cleared from the circulation without untoward consequences. Persistent elevation of lactate levels may occur with chronic disorders such as severe congestive heart failure, pulmonary disease, liver disease, and diabetes mellitus. These levels are generally well-tolerated. To identify the patient in whom an increased lactate level is significant, the physician must assess the clinical state and correlate it with the extent to which increased lactate and hydrogen ion levels contribute to clinical abnormalities.
A presumptive diagnosis of lactic acidosis can be made in many instances. This diagnosis is based upon the recognition of an anion gap acidosis in a patient with a clinical disorder in which lactic acidosis is known to occur. For this impression to be confirmed, other causes of an increased anion gap metabolic acidosis must be excluded, and the plasma lactate concentration must be shown to be elevated.

Anion Gap Acidosis

The anion gap is generally determined by subtracting the concentration of chloride plus bicarbonate ions from the concentration of sodium ion: Na+- (Cl- + HCO3-). The normal value is 12 mEq/L ± 4. Any value greater than 16 mEq/L suggests the presence of an unmeasured ion, usually an accumulation of organic anions. Most patients with lactic acidosis have an anion gap that averages 25 to 30 mEq/L. The major causes of anion gap acidosis in addition to lactic acidosis include diabetic ketoacidosis, uremic acidosis, alcoholic ketoacidosis, and ingestion of the toxins salicylate, methanol, ethylene glycol, paraldehyde, or cyanide (Table -1). Laboratory determinations of the levels of arterial blood gases, electrolytes, glucose, blood urea nitrogen, creatinine, and lactate, and liver function studies and appropriate drug screens, should help establish the correct cause of acidosis.
Particular caution should be used with diabetic and alcoholic patients to ensure that the unmeasured anion is correctly identified. The major organic anion in diabetic and alcoholic ketoacidosis is b-hydroxybutyrate, which is not measured by the serum nitroprusside test. Lactic acidosis and ketoacidosis may occur simultaneously. If lactate levels do not account for the entire increase in the anion gap, ketoacidosis should be suspected, even with a weakly positive acetone test. The bicarbonate level may provide additional help with this differential point. In uncomplicated diabetic ketoacidosis, the increase in the anion gap is identical to the decrease in the bicarbonate concentration, whereas in lactic acidosis, the increase in the anion gap is usually greater than the decrease in the bicarbonate concentration.

Clinical Presentation

The clinical findings in lactic acidosis are nonspecific. The onset may be abrupt, often occurring over several hours. Generally the patient appears ill. Hyperventilation or Kussmaul's respiration is the most constant feature. The level of consciousness may vary from lethargy to coma. Vomiting and abdominal pain sometimes occur. Hypotension and evidence of hypoxia occur with type A lactic acidosis but not with type B.
Laboratory abnormalities that occur during lactic acidosis include elevated lactate levels, increased anion gap, hyperkalemia, decreased bicarbonate levels, and decreased pH unless altered by compensatory alkalosis. Serum potassium concentrations are most likely to be elevated in those patients with underlying renal insufficiency or tissue destruction. Marked hyperphosphatemia and hyperuricemia may be seen. The white blood cell count is usually elevated and may reach leukemoid proportions. Hypoglycemia has also been reported, especially in conjunction with liver disease.

Classification of Lactic Acidosis

Lactic acidosis is classified on clinical grounds and occurs in two principal clinical settings. According to Cohen and Woods’ classification, type A lactic acidosis occurs with clinically evident tissue anoxia, such as during shock or severe hypoxia. Type B lactic acidosis includes all other forms, those in which there is no evidence of tissue anoxia (Table -2). Spontaneous or idiopathic lactic acidosis has been described but is now felt to be nonexistent. Recognition of an increasing array of disorders in which lactic acidosis can occur without evident tissue anoxia has virtually eliminated this category. A new metabolic disorder, d-lactic acidosis, has been described. It occurs in patients with anatomically or functionally shortened small bowel. Bacterial fermentation produces d-lactic acid, which can be absorbed and cause an increased anion gap acidosis and stupor or coma. The plasma levels of l-lactate are normal. Treatment with neomycin or vancomycin results in correction of the metabolic abnormalities.

Type A Lactic Acidosis

This is the most common form of lactic acidosis seen in the emergency department and is most often due to shock. Hemorrhagic, hypovolemic, cardiogenic, or septic shock have been shown to cause lactic acidosis. The pathogenesis of lactic acidosis during shock is inadequate tissue perfusion with subsequent anoxia and lactate and hydrogen ion accumulation. Clearance of lactate by the liver is reduced because of decreased splanchnic and hepatic artery perfusion, and hepatocellular ischemia. At a pH of around 7.0 or less, the liver and kidneys may become organs of lactate production.
The association between shock and lactic acidosis is so common that a presumptive diagnosis can be made in a critically ill patient in shock who suddenly develops severe hyperventilation and an increased anion gap acidosis. Treatment should be directed toward correction of the cause of shock. In general, the higher the lactate level, the higher the mortality.
Hypoxia may also cause type A lactic acidosis. The hypoxia must be acute and severe. Adaptations such as polycythemia, diminished hemoglobin affinity for oxygen, and increased tissue extraction of oxygen protect patients with chronic, stable lung disease from developing lactic acidosis.
These patients may not develop significant lactic acidosis until an arterial PO2 of 30 to 35 mmHg is reached. In patients with a diminished ability to compensate for a respiratory insult, lactic acidosis may arise at considerably higher arterial oxygen tensions. Acute asphyxiation, pulmonary edema, status asthmaticus, acute exacerbation of chronic obstructive pulmonary disease, and displacement of oxygen by carboxyhemoglobin, sulfhemoglobin, or methemoglobin have been associated with lactic acidosis.

Type B Lactic Acidosis

Type B lactic acidosis includes all forms in which there is no clinical evidence of tissue anoxia. This form may occur abruptly, over a few hours. The diagnosis may be missed or delayed because of no clear antecedent event, or because of lack of familiarity with the disorders associated with type B lactic acidosis. The mechanisms by which these disorders predispose to lactic acidosis are not well understood. By definition, the cardiovascular function is not impaired and the blood pressure is not decreased. Subclinical, regional underperfusion of tissue has been suggested as a possible cause. In many cases of severe type B lactic acidosis, circulatory insufficiency may occur after a few hours, making this condition clinically indistinguishable from type A lactic acidosis. Type B lactic acidosis is divided into three subgroups.

Type B1

Type B1 lactic acidosis comprises those cases that occur in association with other medical disorders such as diabetes, renal and hepatic disease, infection, neoplasia, and convulsions. There is no clear causal relation between diabetes and lactic acidosis, but the association between them has been noted by many authors. Massive hepatic necrosis and cirrhosis are associated with lactic acidosis. Decreased lactate clearance by the liver because of insufficient liver tissue for gluconeogenesis may be the cause. Acute and chronic renal insufficiency is commonly associated with lactic acidosis but is probably not a cause in its own right. Some patients with severe infections, especially bacteremia, develop lactic acidosis for unknown reasons. Myeloproliferative disorders such as leukemia, multiple myeloma, generalized lymphoma, and Hodgkin's disease are associated with lactic acidosis. Grand mal seizures may result in lactic acidosis because of muscular hyperactivity and probably hypoxia. Lactic acidosis in Reye's syndrome has been reported. A close correspondence between the stage of coma and lactate levels has been noted.

Type B2

This subgroup includes cases of lactic acidosis due to drugs, chemicals, and toxins. This category was formerly dominated by the oral hypoglycemic agent phenformin, which has been withdrawn from U.S. markets. Ethanol is currently the most common drug associated with lactic acidosis. During the oxidation of alcohol, NADH levels increase, causing utilization of the pyruvate-lactate pathway for the reoxidation of NADH. This reaction produces a moderate increase in the lactate level. In the presence of other causes of lactic acidosis, ethanol ingestion may cause increased acidosis. Other drugs associated with lactic acidosis include fructose; sorbitol; excess amounts of epinephrine and other catecholamines; methanol; and possibly salicylates. Many other drugs have also been implicated as causally related to lactic acidosis.

Type B3

This form of lactic acidosis is rare and is due to inborn errors of metabolism such as type I glycogen storage disease (glucose-6 phosphatase deficiency) and hepatic fructose-biphosphatase deficiency. These congenital lactic acidoses include defects in gluconeogenesis, the pyruvate dehydrogenase complex, the krebs cycle, and cellular respiratory mechanisms.

Treatment

The basic therapeutic goals in treatment of lactic acidosis are to identify and correct the underlying cause of the lactic acid accumulation and to counteract the deleterious effects of the acidosis.
The specifics of therapy depend upon the cause. Shock and hypoxia must be corrected as soon as possible. Adequate ventilation is imperative. Restoration of blood pressure, cardiac output, and tissue perfusion with well-oxygenated blood is essential. Volume replacement with fluids, plasma expanders, or blood, as indicated, should be instituted. Vasopressors should probably be avoided as they may decrease tissue perfusion and worsen the acidosis. Low cardiac output states should be treated with inotropic compounds along with afterload-reducing agents. Catecholamines are glycogenolytic and may enhance lactic acid production. In type B lactic acidosis, the underlying disorder may not be readily identifiable or amenable to therapy. Drugs known to be associated with lactic acidosis should be discontinued, and infection must be aggressively treated.

Sodium bicarbonate

Treatment of acidosis with intravenous sodium bicarbonate (NaHCO3) has been a mainstay of therapy for lactic acidosis. The purpose of this therapy is to reverse the untoward effects of acidosis and allow time for other therapeutic modalities to correct the cause of the acidosis. If the cause of lactic acidosis can be quickly corrected, such as with respiratory failure or pulmonary edema, alkali therapy may not be needed. The undesirable effects of acidosis include depression of myocardal contractility and decreased cardiac output at a pH below 7.1. Arteriolar dilatation and hypotension may occur when the blood pH falls below 7.0. Additionally, a pH below 7.0 impairs hepatic utilization of lactate and may induce production of lactate by the liver and kidneys. These effects may be the cause of the cardiovascular collapse that occurs during the course of type B lactic acidosis.
Several authors have suggested that alkali administration may not only lack benefit but actually be deleterious in the treatment of lactic acidosis. This position is based upon experimental animal studies and the reevaluation of the use of sodium bicarbonate in the treatment of such conditions as diabetic ketoacidosis and cardiopulmonary arrest. This question will most likely remain unresolved for some time. Until an efficacious alternative is identified, sodium bicarbonate will continue to be used in conjunction with cause-specific measures.
In general, sodium bicarbonate should be given when the pH is 7.1 or less. The smallest possible amount of bicarbonate that will return the systemic pH to hemodynamically safe levels (e.g., pH of 7.2) should be used. Frequent monitoring of the acid-base status during bicarbonate therapy is essential for appraisal of additional bicarbonate requirements. Some undesirable effects of sodium bicarbonate include fluid and sodium overload, hyperosmolarity, alkaline overshoot which could increase lactate production, displacement of the oxyhemoglobin dissociation curve to the left, and paradoxical cerebrospinal fluid acidosis.
The approximate dose of bicarbonate required to correct the acidosis can be calculated from the following formula:

HCO3 deficit =(25 mEq/L HCO3 -measured HCO3) x 0.5(body weight in kg)

This equation is based upon the assumption that bicarbonate distributes in a space equal to 50 percent of the body weight in kilograms. The apparent space of distribution for bicarbonate is enlarged in hypobicarbonatemic states; thus, using 50 percent body weight to calculate the space for distribution of bicarbonate may underestimate the bicarbonate requirements.
Some patients may require massive amounts of sodium bicarbonate to correct acidemia. Those unable to tolerate fluid and sodium overload can be treated with a bicarbonate infusion, potent loop diuretic, or tris(hydroxymethyl)aminomethane (THAM). Hyperosmolarity can be reduced by adding 3 to 4 ampoules of NaHCO3 (44 mEq/L) to 1 L of 5% dextrose and water. This solution provides 132 to 176 mEq/L, respectively. Use of a potent loop diuretic creates intravascular space for fluid and sodium. A diuretic should be given in whatever dose is required to maintain a brisk diuresis (300 to 500 mL/h). Urinary sodium and potassium losses can be measured and replaced along with the urinary volume loss on an equal basis.
Oliguric patients require hemodialysis to permit administration of large amounts of sodium bicarbonate. Standard dialysis baths can be replaced by a bicarbonate bath so that the fluid and sodium chloride removed by the hypertonic solution can be replaced as the bicarbonate salt. Hemodialysis and peritoneal dialysis remove lactate. As there is no evidence that lactate ion per se is harmful, this approach is unnecessary. Removal of lactate, however, can minimize the rebound alkalosis that often occurs after correction of the acidosis.
There is often a delay of many hours between the return of the pH to the normal range and a fall in the blood lactate level. The bicarbonate infusion can be decreased after several hours of a normal pH. If the pH begins to drop, the bicarbonate infusion can be increased. When the pH stabilizes in an acceptable range, the infusion can be discontinued. As always, the clinical status of the patient is the best parameter to follow during recovery.

Additional Treatment

A variety of other therapies have been advocated in treatment of lactic acidosis. These include insulin, glucose, thiamine, methylene blue, vasodilator drugs such as sodium nitroprusside, carbicarb, and the experimental drug dichloroacetate. Most authors do not favor the use of insulin, or insulin in conjunction with glucose, in treatment of lactic acidosis. Insulin may be indicated in a diabetic patient with concomitant lactic acidosis or in a diabetic with an unexplained increased anion gap acidosis. Insulin therapy in these instances should be based upon individual need. Glucose infusion in the setting of hypoglycemia and lactic acidosis has been reported to correct the lactic acidosis.
Thiamine is a necessary cofactor for the enzyme that catalyzes the first step in the oxidation of pyruvate. This vitamin should be given to alcoholic patients with lactic acidosis, but a role for thiamine therapy in other patients has not been established. Methylene blue is a redox dye that is capable of accepting H+ and thereby oxidizing NADH2 to NAD+ and theoretically limiting the conversion of pyruvate to lactate. Clinical trials have not supported the benefit of this drug. Vasodilator therapy is based upon the premise that tissue perfusion improves with reduced peripheral vascular resistance and increased cardiac output. The value of vasodilator agents in treatment of lactic acidosis remains to be proved.
Carbicarb is an equimolar solution of sodium bicarbonate and sodium carbonate. This mixture buffers hydrogen ion without the net generation of CO2. Carbicarb also consumes excess CO2 to yield more bicarbonate buffer. The deleterious effect of an increase in tissue PCO2 is avoided. Experimentation with carbicarb is ongoing and no clear clinical benefit has been demonstrated.
Dichloroacetate (DCA) is an experimental drug that increases the activity of pyruvate dehydrogenase, and this promotes the oxidation of glucose, pyruvate, and lactate and thus reduces blood lactate levels. Since oxygen is required for this metabolic process, DCA has no role in treatment of type A lactic acidosis. Its role in therapy for type B lactic acidosis may be limited by the increased ketosis and neurologic complications that occur with its use.
The fact that so many experimental therapies have been tried in lactic acidosis reflects the poor outcome of this disorder with the use of current treatment. The mortality of patients with type A lactic acidosis is approximately 80 percent; with type B it is 50 to 80 percent. Earlier recognition and correction of the underlying disorder responsible for the lactic acidosis is the best hope for reduction of this high mortality.

BIBLIOGRAPHY:
1)Kreisberg RA: Pathogenesis and management of lactic acidosis. Annu Rev Med 35:181, 1984.
2)Narins RG, Cohen JJ: Bicarbonate therapy for organic acidosis: The case for its continued use. Ann Intern Med 106:615, 1987.
3)Oliva PB: Lactic acidosis. Am J Med 48:209, 1970.
4)Park R, Arieff AI: Lactic acidosis: Current concepts. Clin Endocrinol Metab 12:339, 1983.
5)Stacpoole PW, Wright EC, Baumgartner TG, et al: A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. NEngl J Med 327:1564, 1992.

TABLE
Causes of Increased Anion Gap Metabolic Acidosis

Increased endogenous organic acids: Ingestion of toxins:
Diabetic ketoacidosis Salicylates
Alcoholic ketoacidosis Methanol
Lactic acidosis Ethylene glycol
Decreased excretion of organic and inorganic acids: Paraldehyde
Renal failure (uremia) Cyanide

TABLE
Classification of Lactic Acidosis

Type A:
Clinically evident tissue anoxia (e.g., shock, hypoxia)
Type B:
Various common disorders
Diabetes mellitus
Renal failure
Liver disease
Infection
Leukemia and certain other malignant conditions
Convulsions
Drugs, toxins
Biguanides (phenformin)
Ethanol
Fructose and other saccharides
Methanol
Various other drugs
Hereditary forms
Type I glycogen storage disease
Fructose-biphosphatase deficiency
Subacute necrotizing encephalomyelopathy (Leigh's syndrome)
Methylmalonic aciduria
Others