Acidosis

(1)

Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

Keywords

LactateHyperlactatemiaTissue hypoxiaWarburg effectMetformin-associated lactic acidosis (MALA)Antiretroviral agentsLinezolidPropofol

Although lactic acid and lactate are used interchangeably, it is the latter that circulates predominantly in the body at pH of 7.4. Lactate occurs in two stereoisomers or enantiomers: L-lactate and D-lactate (Fig. 5.1). L-lactate is the predominant stereoisomer in healthy subjects. D-lactate is usually synthesized from bacteria. In clinical laboratories, only L-lactate (simply lactate) is measured.

../images/480755_1_En_5_Chapter/480755_1_En_5_Fig1_HTML.png — Fig. 5.1

Stereoisomers of lactate

Lactate is formed from pyruvate, which is an intermediate metabolic product of anaerobic glycolysis. Thus, the major source of lactate is glucose. Another source of lactate production is alanine (16–20%), which is converted to pyruvate via alanine aminotransferase (Fig. 5.2). Pyruvate then enters the citric acid cycle and oxidized to form CO₂ and water (Fig. 5.2). During this process, ATP is generated. Glycolysis occurs in cytoplasm, whereas oxidation occurs in mitochondria. Lactate is also converted into glucose via gluconeogenesis. Thus, lactate is cleared from body by its conversion to pyruvate and glucose.

../images/480755_1_En_5_Chapter/480755_1_En_5_Fig2_HTML.png — Fig. 5.2

Simplified diagram illustrating lactate formation from pyruvate occurring via glycolysis (cytoplasm) and oxidation of pyruvate to CO₂ and water (mitochondria). LDH lactate dehydrogenase, ALT alanine aminotransferase

Approximately 20 mmol/kg/day of lactate is produced (~1300 mmol in a 70 kg man) in tissues such as skin (350 mmol), erythrocytes (302 mmol), brain (235 mmol), skeletal muscle (218 mmol), GI tract (115 mmol), and platelets and white blood cells (70 mmol). Lactate is utilized (metabolized) in the liver (722 mmol), kidney (386 mmol), heart (80 mmol), and other organs (102 mmol). Despite this high daily production of lactate, its circulating levels remain <1.5 mmol/L because of extensive utilization, as stated above. Lactic acidosis develops only when lactate production exceeds its utilization or when utilization of lactate is greatly reduced despite normal production, as in liver failure.

Lactic acidosis is a serious condition and carries increased morbidity and mortality. There is a linear relationship between lactate levels and mortality, and higher levels predict mortality. There are two types of lactic acidosis. The most common one is L-lactic acidosis, and less frequent one is D-lactic acidosis, and both types are presented below.

l-Lactic Acidosis

Production

As stated above, lactate is formed only from pyruvate (Fig. 5.2). This conversion is facilitated by lactate dehydrogenase (LDH). In this reaction, pyruvate is reduced to lactate, which requires oxidation of reduced nicotinamide adenine dinucleotide (NADH) to oxidized nicotinamide adenine dinucleotide (NAD⁺). NADH/NAD⁺ ratio determines the conversions between pyruvate and lactate. The normal lactate to pyruvate ratio is 10:1. As shown in the reaction below, lactate can be oxidized to pyruvate by LDH where NAD⁺ is reduced to NADH

../images/480755_1_En_5_Chapter/480755_1_En_5_Figa_HTML.png

From the above reaction, excess lactate production can be expected by the following pathophysiologic processes:

1.

Increased glycolysis and pyruvate production, which are caused by intravenous (i.v.) glucose or epinephrine infusion, and metabolic or respiratory alkalosis. Alkalosis stimulates glycolysis by increasing the activity of a rate-limiting enzyme of glycolysis, phosphofructokinase (PFK). Acidosis and ATP inhibit PFK, leading to less lactate production
2.

An increase in NADH/NAD⁺ ratio due to hypoxic conditions
3.

Combination of above two processes

Hyperlactatemia Vs. Lactic Acidosis

Hyperlactatemia is defined as serum lactate levels of 2–5 mmol/L without acidosis. It usually occurs in conditions of adequate tissue perfusion and tissue buffering capacity. Hyperlactatemia is seen in conditions of activated aerobic glycolysis due to stress, elevated epinephrine levels with the use of β₂-adrenergic agonists, asthma, alkalemia, and certain cytokine-stimulated glycolysis. Some drugs (antiretrovirals) may also cause hyperlactatemia. Serum [HCO₃ ⁻] may be slightly lowered by increased lactate levels, but the systemic pH may be minimally altered. Removal of offending agent or correction of clinical condition may improve hyperlactatemia.

In contrast to hyperlactatemia, lactic acidosis is seen in patients with global tissue hypoxia and is associated with severe consequences. Normalization of lactate levels is rather difficult (see Treatment).

Causes

Causes can be either acquired or inherited. Most of the causes in adults are acquired (see Tables 5.1 and 5.2).

1.

Generally, lactic acidosis is divided into two types: type A and type B acidosis
2.

Type A acidosis results from generalized or regional tissue hypoxia
3.

Type B acidosis results from biochemical abnormalities due to systemic diseases or toxins. Based on the underlying etiology, some authorities may divide type B lactic acidosis into type B1 (systemic diseases), type B2 (drugs and toxins), and type B3 (inherited)
4.

Note that both type A and type B conditions can be superimposed on one another rather commonly in any patient (metformin use in CHF patient)

Table 5.1

Causes of type A lactic acidosis (clinical evidence of tissue hypoxia)

Cause	Mechanism(s)
Shock
Septic shock	Hypotension
Hypovolemic shock	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Cardiogenic shock	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Hemorrhagic shock	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Severe tissue hypoxia	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Severe regional hypoperfusion due to hypotension	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Severe anemia (<4.0 g/dL)	Tissue hypoxia
Severe asthma	Respiratory alkalosis stimulation of glycolysis and lactate production, tissue hypoxia, β-adrenergic stimulation, and lactate production
Carbon monoxide poisoning	Carbon monoxide binds more avidly to Hgb than O₂, leading to less delivery to tissues and hypoxia, inhibition of electron transport system, ↓ ATP, ↑ anaerobic glycolysis

Table 5.2

Causes of type B lactic acidosis (no clinical evidence of tissue hypoxia)

Causes	Mechanism(s)
Systemic disease (B1)
Liver disease	↓ Lactate metabolism, ↓ pyruvate dehydrogenase complex (PDC)^a activity, respiratory alkalosis, and hypoglycemia may precipitate lactate production
Diabetes mellitus	Presence of microvascular disease and atherosclerosis compromising circulation, drug use such as metformin, ↓ PDC activity
Renal failure and renal replacement therapies	Stimulation of lactate production by alkalinization due to HCO₃ ⁻, dialysate baths containing lactate
Malignancy	Lymphomas, leukemias, and carcinomas (breast, lung, colon, pancreas), production of lactate by tumor cells via ↑ anaerobic glycolysis, ↑ cytokine production, hypoxia-inducible factor
ATP depletion	↑ Anaerobic glycolysis
Thiamine deficiency	Inhibits PDC activity, thereby limiting glucose metabolism to glycolysis only
Seizures	Increased muscle activity, compromised blood flow, and tissue hypoxia
Hypoglycemia	Inhibits lactate uptake by liver, ↑ epinephrine release causing increased production of pyruvate
Drugs/toxins (B2)
Metformin	Promotes lactate production from glucose in small intestine, ↑ NADH/NAD⁺ ratio, inhibits gluconeogenesis from lactate, inhibition of mitochondrial oxidative phosphorylation, patients with renal, hepatic, and cardiac failure are at risk
Ethanol	Impairs gluconeogenesis from lactate to glucose, depletes NAD⁺ favoring lactate accumulation
Methanol	Toxic products of methanol (formaldehyde, formic acid) inhibits oxidative phosphorylation and ATP synthesis
Ethylene glycol	↑ NADH/NAD⁺ ratio during metabolism of ethylene glycol via alcohol dehydrogenase
Propylene glycol	Used as solvent (during infusion of lorazepam, nitroglycerine, or topical application of silver sulfadiazine), produces lactate during its metabolism via alcohol dehydrogenase. This reaction produces high NADH/NAD⁺ ratio
Salicylates	Respiratory alkalosis-stimulated lactate production, inhibition of oxidative phosphorylation
Cyanide poisoning	Inhibition of oxidative phosphorylation, ↓ ATP production, ↑ glycolysis, ↑ NADH/NAD⁺ ratio, leading to pyruvate conversion to lactate production
Catecholamines	Epinephrine increases glycolysis and inhibits pyruvate formation from lactate. Increased vasoconstriction of skin, skeletal muscle, and splanchnic circulation with high concentrations of epinephrine and norepinephrine. Lactic acidosis may be the initial finding in pheochromocytoma
Cocaine	Increased vasoconstriction
Antiretrovirals (didanosine, zidovudine, stavudine, tenofovir)	Inhibition of mitochondrial DNA synthesis, ↓ ATP production, ↑ glycolysis
Linezolid	Mitochondrial toxicity
Propofol	Sedative, increased production of lactate on high doses due to uncoupling of oxidative phosphorylation
Hereditary or acquired enzyme defects (B3)	(see below)

^aPyruvate dehydrogenase complex is an enzymatic system that converts pyruvate to acetyl-CoA in mitochondria and hence to CO₂ and H₂O via citric acid cycle

Selected Conditions of L-Lactic Acidosis

Tissue Hypoxia

The most important cause of type A lactic acidosis is tissue hypoxia, which may be due to decreased perfusion or decreased O₂ content. Shock of any etiology leads to hypotension, leading to lactic acid production. Other causes of tissue hypoxia include severe anemia, severe asthma, and carbon monoxide poisoning.

Sepsis and septic shock are due to macro- and microcirculatory dysfunction with decreased O₂ and nutrient delivery to the peripheral tissues. The resultant hypoxia causes inhibition of mitochondrial oxidative phosphorylation and reduction in ATP synthesis as well as an increase in NADH/NAD⁺ ratio. This causes high lactate production, which is considered a useful marker of tissue hypoxia and a plan for fluid resuscitation in sepsis and septic shock.

During sepsis, insulin resistance occurs and gluconeogenesis increases. Also, whole-body glucose uptake by noninsulin-mediated mechanisms occurs. Glucose uptake by tissues such as skeletal muscle is mediated by cytokines such as tumor necrosis factor α and interleukin 6. Insulin resistance, gluconeogenesis, and cytokine stimulation of glucose uptake promote glycolysis and production of lactate from pyruvate.

Although elevated levels of lactate from anaerobic glycolysis due to tissue hypoxia have been reported to carry poor prognosis in sepsis, it was proposed that hyperlactatemia may also be caused by aerobic (not related to hypoxia) glycolysis. For example, sepsis causes high circulating levels of epinephrine, which stimulates Na/K-ATPase of skeletal muscle membrane and causes increased aerobic glycolysis. Thus, a major portion of the increased lactate levels may be attributed to aerobic glycolysis. This suggests that lactate is an unreliable marker of sepsis. Despite this critique, lactate is simple to measure, and its increasing levels during uncontrolled sepsis and decreasing levels to antibiotic therapy make it a dependable marker for sepsis.

Malignancy

In 1923, Otto Warburg demonstrated that cancer cells have the ability to increase their glycolytic activity and generate excessive production of lactic acid in the presence of O_2. This phenomenon of aerobic glycolysis was subsequently named “Warburg effect.” Otto Warburg also observed that glucose uptake by tumor cells was much higher than normal cells and tumor cells metabolized more glucose to lactate. Indeed it was found that lactate levels were much higher in blood vessels leaving the tumor cells than blood vessels entering the tumor cells. Later, it was observed that hematologic malignancies such as lymphomas and leukemias generate very high levels of lactic acid. Patients with very high levels of lactic acid had poor prognosis. Other malignancies, including melanomas, multiple myeloma, lung cancer, sarcomas, breast cancer, as well as others, were also found to generate and release lactic acid into the surrounding environment.

Several mechanisms for increased production of lactic acid by cancer cells have been demonstrated:

1.

Glucose uptake by cancer cells is enhanced. Insulin-like growth factor-1 and tumor necrosis factor α, which are increased by cancer cells, stimulate glucose uptake
2.

Hexokinase and other glycolytic enzymes are overexpressed in many tumors
3.

Expression of transcription factors such as hypoxia-inducible transcription factor-1 (HIF-1) and c-Myc is enhanced in several cancer tissues. HIF-1 activates the genes encoding glycolytic enzymes, glucose, and lactate transporters, leading to enhanced glycolysis and lactic acid production
4.

HIF-1 indirectly inhibits pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA for mitochondrial oxidation, thereby driving the accumulated pyruvate to lactate
5.

Thiamine deficiency caused by tumor cells and chemotherapy (methotrexate). Thiamine is a cofactor for PDH, and its deficiency causes decreased oxidative phosphorylation and energy (ATP) production

Lactic acid that is accumulated in cancer cells is transported from inside to outside by proton-linked monocarboxylate transporters (MCTs). Of the 14 MCT isoforms, only MCT1 and MCT4 are involved in lactic acid transport. Lactate, pyruvate, β-hydroxybutyrate, and acetoacetate are short-chain monocarboxylates. Once lactic acid is outside the cell, the pH of the extracellular microenvironment becomes severely acidic (in the range of 6.6), which promotes progression of tumor and imparts poor prognosis in several human cancers. MCT1 and MCT4 stimulate glycolysis in cancer cells in addition to their participation in lactic acid transport. Thus, inhibitors of MCT1 and MCT4 may decrease aerobic glycolytic pathway and lower lactate production. In addition to high activity of MCTs, increased activity of lactate dehydrogenase that converts pyruvate to lactate has been reported in cancer cells.

Treatment as well as prevention of malignancy-induced excess lactic acid is currently limited. Thiamine administration may be helpful. Also, inhibitors of lactate dehydrogenase and MCTs, once available, may play a significant role in preventing excess production of lactic acid in various human cancers.

Metformin-Associated Lactic Acidosis (MALA)

Metformin is a biguanide and is the recommended choice of oral hypoglycemic agent for patients with type 2 diabetes. Despite its widespread use, the occurrence of severe or fatal lactic acidosis is rather uncommon. The incidence of lactic acidosis at therapeutic levels of metformin is 3–5 cases per 100,000 patient years. Metformin lowers glucose by inhibition of hepatic gluconeogenesis and promoting glucose uptake by skeletal muscle. Additional mechanisms include interaction with the incretin axis through the action of glucagon-like peptide 1 and also antagonizing the actions of glucagon. Metformin is considered safe if used properly. Most of the drug is metabolized by the kidney with partial fecal elimination. Therefore, the dose requirements in patients with severe renal failure are different compared to a patient with normal renal function.

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