Causes of lactic acidosis

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Causes of lactic acidosis
Authors
Burton D Rose, MD
Theodore W Post, MD
Section Editor
Richard H Sterns, MD
Deputy Editor
Alice M Sheridan, MD


Last literature review version 16.2: May 2008 | This Topic Last Updated: October
3, 2007 (More)
INTRODUCTION Lactic acidosis is the most common cause of metabolic acidosis in
hospitalized patients. It is associated with an elevated anion gap and a plasma lactate
concentration above 4 meq/L. Impaired tissue oxygenation, leading to increased
anaerobic metabolism, is usually responsible for the rise in lactate production. ( See
"Approach to the adult with metabolic acidosis").
The pathophysiology and causes of lactic acidosis will be reviewed here. The possible role
of bicarbonate therapy in such patients is discussed separately. ( See "Bicarbonate
therapy in lactic acidosis").
PATHOPHYSIOLOGY A review of the biochemistry of lactate generation and
metabolism is important in understanding the pathogenesis of lactic acidosis. Both
overproduction and underuse of lactate appear to be operative in most patients.
Lactic acid is derived from the metabolism of pyruvic acid; this reaction is catalyzed by
lactate dehydrogenase and involves the conversion of NADH into NAD+ (reduced and
oxidized nicotine adenine dinucleotide, respectively). Normal subjects produce 15 to 20
mmol/kg of lactic acid per day, most of which is generated from glucose via the glycolytic
pathway or from the deamination of alanine [ 1,2] .
Lactic acid is rapidly buffered, in part by extracellular bicarbonate, resulting in the
generation of lactate. In the liver and, to a lesser degree, in the kidney, lactate is
metabolized back to pyruvate, which is then converted into either carbon dioxide and
water (80 percent, catalyzed in part by pyruvate dehydrogenase) or glucose (20 percent,
catalyzed in part by pyruvate carboxylase). Both of these processes result in the
regeneration of the bicarbonate lost in the initial buffering of lactic acid.
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Excess lactate can accumulate when there is increased lactate production and/or
diminished lactate utilization [ 1-4] . Three mechanisms can underlie the accumulation
[ 1,2] :
Enhanced pyruvate production
Reduced pyruvate conversion to carbon dioxide and water or to glucose
An altered redox state within the cell in which pyruvate is preferentially converted
into lactate
In certain disorders, the primary role of lactate overproduction is clear. As an example,
plasma lactate levels may transiently be as high as 15 meq/L during a grand mal seizure
[ 5] , and 20 to 25 meq/L with maximal exercise, with the systemic pH falling to as low as
6.80 [ 6,7] . Studies in these patients have demonstrated rapid recovery of acid-base
balance with a maximum rate of lactate utilization that can reach 320 meq/h [ 1] .
The high metabolic capacity for lactate suggests that there must be some component of
decreased utilization in those disorders in which lactate overproduction occurs more
slowly. The importance of impaired metabolism is illustrated by the observation that
infusion of lactic acid into normal animals at a rate similar to the rate of overproduction in
shock is associated with increased hepatic utilization of lactate with little reduction in pH
[ 4] . In shock, for example, the reduction in perfusion to the liver and an associated
intracellular acidosis may combine to substantially diminish hepatic lactate metabolism
[ 3,4,8] .
CAUSES The normal plasma lactate concentration is 0.5 to 1.5 meq/L. Lactic acidosis
is considered to be present if the plasma lactate concentration exceeds 4 to 5 meq/L,
even among patients without a systemic acidosis.
The causes of lactic acidosis can be divided into those associated with impaired tissue
oxygenation (type A) and those in which a systemic impairment in oxygenation is not
apparent (type B) ( show table 1).
Type A lactic acidosis Most cases of lactic acidosis are due to marked tissue
hypoperfusion in shock (due to hypovolemia, cardiac failure, or sepsis) or during a
cardiopulmonary arrest [ 1,2,9,10] . In some of these patients, concurrent respiratory
acidosis contributes to the acidemia [ 9] . ( See "Shock in adults: Types, presentation,
and diagnostic approach" and see "Clinical manifestations and diagnosis of cardiogenic
shock complicating acute myocardial infarction").
The clinical manifestations of shock include:
A reduction in systemic blood pressure, the degree of which may be minimized by
marked vasoconstriction
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Cool, clammy extremities, with the exception of the flushed, hyperemic skin of
early septic shock
Oligoanuria
Impaired mental status
The prognosis is generally poor unless tissue perfusion can be rapidly restored. ( See
"Treatment of severe hypovolemia or hypovolemic shock in adults" and see "Treatment
and prognosis of cardiogenic shock complicating acute myocardial infarction" and see
"Management of severe sepsis and septic shock in adults").
Type B lactic acidosis The findings of systemic hypoperfusion are not apparent in
type B lactic acidosis. Among the mechanisms that may be involved are a toxin-induced
impairment of cellular metabolism or regional areas of ischemia.
Diabetes mellitus and metformin Biguanide therapy in type 2 diabetes with
phenformin in the past or currently with metformin can lead to type B lactic acidosis
[ 11,12] . Serum lactate concentrations are usually less than 2 meq/L with metformin
therapy, values that are not clinically important. More serious lactic acid accumulation
occurs with superimposed shock or in the presence of predisposing conditions to
metformin toxicity such as renal insufficiency (serum creatinine concentration above 1.5
mg/dL [133 mol/L]) or concurrent heart failure requiring pharmacologic therapy, liver
disease, or alcohol abuse [ 11] .
Lactic acidosis remains a problem in part because a number of patients treated with
metformin (22 percent in one review) have one or more of these contraindications [ 13] .
( See "Metformin in the treatment of diabetes mellitus", section on Lactic acidosis).
The incidence of lactic acidosis in metformin users appears to be very low overall
[ 12,14,15] . In a review of 11,800 patients treated with metformin for a mean of about
two years in Saskatchewan, Canada, only two patients developed lactic acidosis
(incidence 9 cases per 100,000 years of exposure) [ 12] . Both patients had other factors
that could have contributed to the acidosis.
This finding is consistent with a 2006 systematic review of 206 comparative trials or
cohort studies with almost 48,000 patient-years of metformin exposure [ 15] . There
were no cases of fatal or nonfatal lactic acidosis. Almost one-half of the studies allowed
inclusion of patients with a serum creatinine above 1.5 mg/dL (133 mol/L) and almost
all allowed inclusion of patients with at least one contraindication to metformin therapy.
However, the number of patients who actually had these contraindications was not
presented.
In summary, the risk of lactic acidosis in the overall population of patients with type 2
diabetes treated with metformin is very low. Although only patients with one or more of
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the predisposing factors cited above are at risk, the incidence of lactic acidosis in these
patients is not known and may be low in patients with borderline risk factors. This is an
important issue because of the benefits of metformin in the treatment of type 2 diabetes
mellitus may outweigh the risk in such patients. ( See "Metformin in the treatment of
diabetes mellitus").
In addition to metformin therapy, a moderate degree of lactic acidosis may be seen in
some patients with diabetic ketoacidosis [ 1,16] . How this occurs in not clear although
marked hypovolemia is likely to play an important role. ( See "Epidemiology and
pathogenesis of diabetic ketoacidosis and hyperosmolar hyperglycemic state").
Malignancy The pathogenesis of the lactic acidosis that rarely occurs in leukemia,
lymphoma, and solid malignancies is unclear [ 17-21] . Anaerobic metabolism due to
dense clusters of tumor cells and/or metastatic replacement of the hepatic parenchyma
have been proposed, but lactic acidosis has occurred in patients with relatively small
tumor burdens [ 17,19] . Direct lactate production by the neoplastic cells has also been
suggested, but this would not explain the rarity of tumor-induced lactic acidosis. Thiamine
or riboflavin deficiency has also been suggested in some of these cases [ 21] . Regardless
of the mechanism, removal of the tumor (by chemotherapy, irradiation, or surgery) leads
to correction of the acidosis [ 17,19-21] . ( See "Complications of acute myeloid
leukemia").
Alcoholism A mild degree of lactic acidosis may be seen with alcoholism. Lactate
production is usually normal but lactate utilization is diminished because of impaired
hepatic gluconeogenesis. Although lactate levels generally do not exceed 3 meq/L in this
setting, alcohol ingestion can potentiate the severity of other disorders that are
associated with the overproduction of lactate. ( See "Alcoholic and fasting ketoacidosis").
HIV infection Given the increased propensity to serious infection, sepsis-induced
lactic acidosis can occur in patients with AIDS. There are, in addition, cases in which lactic
acidosis appears to result from drug-induced mitochondrial dysfunction in the absence of
sepsis or hypoperfusion (type B lactic acidosis). These disorders are described separately.
( See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors").
D-lactic acidosis A unique form of lactic acidosis can occur in patients with jejunoileal
bypass or, less commonly, small bowel resection or other cause of the short bowel
syndrome. In these settings, glucose and starch are metabolized in the colon into D-lactic
acid, which is then absorbed into the systemic circulation [ 22-24] . The ensuing acidemia
tends to persist, since D-lactate is not recognized by L-lactate dehydrogenase, the
enzyme that catalyzes the conversion of the physiologically occurring L-lactate into
pyruvate. ( See "D-Lactic acidosis").

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REFERENCES

1. Kreisberg, RA. Lactate homeostasis and lactic acidosis. Ann Intern Med 1980;
92:227.
2. Madias, NE. Lactic acidosis. Kidney Int 1986; 29:752.
3. Arieff, AI, Park, R, Leach, WJ, Lazarowitz, VC. Pathophysiology of experimental
lactic acidosis in dogs. Am J Physiol 1980; 239:F135.
4. Arieff, AI, Graf, H. Pathophysiology of type A hypoxic lactic acidosis in dogs. Am J
Physiol 1987; 253:E271.
5. Orringer, CE, Eustace, JC, Wunsch, CD, Gardner, LB. Natural history of lactic
acidosis after grand-mal seizures. A model for the study of an anion-gap acidosis
not associated with hyperkalemia. N Engl J Med 1977; 297:796.
6. Osnes, JB, Hermansen, L. Acid-base balance after maximal exercise of short
duration. J Appl Physiol 1972; 32:59.
7. Lindinger, M, Heigenhauser, GJ, McKelvie, RS, Jones, NL. Blood ion regulation
during repeated maximal exercise and recovery in humans. Am J Physiol 1992;
262:R126.
8. Bersin, RM, Arieff, AI. Improved hemodynamic function during hypoxia with
carbicarb, a new agent for the management of acidosis. Circulation 1988; 77:227.
9. Fulop, M, Horowitz, M, Aberman, A, Jaffe, ER. Lactic acidosis in pulmonary edema
due to left ventricular failure. Ann Intern Med 1973; 79:180.
10. Weil, MH, Afifi, AA. Experimental and clinical studies on lactate and pyruvate as
indicators of the severity of acute circulatory failure (shock). Circulation 1970;
41:989.
11. Gan, SC, Barr, J, Arieff, AI, Pearl, RG. Biguanide-associated lactic acidosis: Case
report and review of the literature. Arch Intern Med 1992; 152:2333.
12. Stang, M, Wysowski, DK, Butler Jones, D. Incidence of lactic acidosis in metformin
users. Diabetes Care 1999; 22:925.
13. Horlen, C, Malone, R, Bryant, B, et al. Frequency of inappropriate metformin
prescriptions. JAMA 2002; 287:2504.
14. McCormack, J, Johns, K, Tildesley, H. Metformin's contraindications should be
contraindicated. CMAJ 2005; 173:502.
15. Salpeter, S, Greyber, E, Pasternak, G, Salpeter, E. Risk of fatal and nonfatal lactic
acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst
Rev 2006; :CD002967.
16. Marliss, EB, Ohman, JL Jr, Aoki, TT, Kozak, GP. Altered redox state obscuring
ketoacidosis in diabetic patients with lactic acidosis. N Engl J Med 1970; 283:978.
17. Sillos, EM, Shenep, JL, Burghen, GA, et al. Lactic acidosis: a metabolic complication
of hematologic malignancies: case report and review of the literature. Cancer
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2001; 92:2237.
18. Fraley, DS, Adler, S, Bruns, FJ, Zett, B. Stimulation of lactate production by
administration of bicarbonate in a patient with a solid neoplasm and lactic acidosis.
N Engl J Med 1980; 303:1100.
19. Nadiminti, Y, Wang, JC, Chou, SY, et al. Lactic acidosis associated with Hodgkin's
disease: response to chemotherapy. N Engl J Med 1980; 303:15.
20. Rice, K, Schwartz, SH. Lactic acidosis with small cell carcinoma. Rapid response to
chemotherapy. Am J Med 1985; 79:501.
21. Friedenberg, AS, Brandoff, DE, Schiffman, FJ. Type B lactic acidosis as a severe
metabolic complication in lymphoma and leukemia: a case series from a single
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22. Stolberg, L, Rolfe, R, Gitlin, N, et al. d-Lactic acidosis due to abnormal gut flora:
diagnosis and treatment of two cases. N Engl J Med 1982; 306:1344.
23. Halperin, ML, Kamel, KS. D-lactic acidosis: Turning sugars into acids in the
gastrointestinal tract. Kidney Int 1996; 49:1.
24. Uribarri, J, Oh, MS, Carroll, HJ. D-lactic acidosis. A review of clinical presentation,
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1998; 77:73.
GRAPHICS
Etiology of lactic acidosis
Increased lactate production
A. Increased pyruvate production
1. Enzymatic defects in glycogenolysis or gluconeogenesis (as with type 1 glycogen storage
disease)
2. Respiratory alkalosis, including salicylate intoxication
3. Pheochromocytoma
B. Impaired pyruvate utilization
1. Decreased activity of pyruvate dehydrogenase or pyruvate carboxylase
a. Congenital
b. Possibly a role in diabetes mellitus, Reye's syndrome
C. Altered redox state favoring pyruvate conversion to lactate
1. Enhanced metabolic rate
a. Grand mal seizure
b. Severe exercise
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c. Hypothermic shivering
d. Severe asthma
2. Decreased oxygen delivery
a. Shock
b. Cardiac arrest
c. Acute pulmonary edema
d. Carbon monoxide poisoning
e. Severe hypoxemia (P
O2
<25 to 30 mmHg)
f. Pheochromocytoma
3. Reduced oxygen utilization
a. Cyanide intoxication ( oxidative metabolism), which may result from cyanide poisoning or,
during a fire, from smoke inhalation of vapors derived from the thermal decomposition of
nitrogen-containing materials such as wool, silk, and polyurethane
b. Drug-induced mitochondrial dysfunction due to zidovudine or stavudine
D. D-Lactic acidosis
Primary decrease in lactate utilization
A. Hypoperfusion and marked acidemia
B. Alcoholism
C. Liver disease
Mechanism uncertain
A. Malignancy
B. Diabetes mellitus, including metformin in the absence of tissue hypoxia
C. Acquired immune deficiency syndrome
D. Hypoglycemia
E. Idiopathic
Although this table has been divided into either increased production or
decreased utilization of lactate, there is considerable overlap among listed
causes.
Reproduced with permission from: Rose, BD, Post, TW. Clinical Physiology of
Acid-Base and Electrolyte Disorders. 5th ed, McGraw-Hill, New York 2001, p.
594. Copyright 2001 McGraw-Hill.
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