#anion gap

Metabolic Acidosis

UAG = urine anion gap

NeGUTive UAG = GUT etiology

*** Paraldehyde is old and rarely used, however Proplylene glycol is used in many medications and more commonly causes metabolic acidosis.

Anion gap (will cover this in more depth with diabetes) is calculated from sodium level – (chloride + bicarbonate). You could do (sodium + potassium) – (chloride + bicarbonate). Potassium contributes so little that it’s often omitted, however. Anion gap means something else is contributing to the acid-base balance, not just the exchange of chloride for bicarbonate, for example.

Metabolic acidosis: Low pH, a low HCO3- concentration. Compensatory hyperventilation that contributes to a decreased pCO2. Most common causes: Inability of kidneys to excrete dietary hydrogen ion load, increase in hydrogen ion generation due to an addition of hydrogen ions or a loss of bicarbonate

Metabolic alkalosis: High pH, a high bicarbonate- concentration, and compensatory hypoventilation that contributes to an increased pCO2. Most common causes: loss of gastric acid from vomiting or nasogastric suction, loss of intravascular volume and chloride from diuretic use. Overtreatment of metabolic acidosis with bicarbonate. Excess of acetate in PN (parenteral nutrition), which becomes metabolized to bicarbonate

A1C distinguishes between diabetes and hyperglycemia associated with metabolic stress

 Protein: Again:

First start by converting the protein intake of the patient (94g in this example) to grams of nitrogen. Second, calculate their nitrogen balance. We find that the patient is in negative nitrogen balance. Nitrogen balance should be the same amount of nitrogen coming into the body as is coming out in the urine. Third: Correct the deficit to get into nitrogen balance. Take that -2g of deficit that they are at (take the minus sign away), and multiply that by 6.25g of protein (1g of nitrogen = 6.25g of protein). Correcting the deficit of nitrogen finds that the patient will require 12.5 more grams of protein just to get into nitrogen balance. Fourth, we still need the patient to be in positive nitrogen balance, so, we increase protein and shoot for 2g more protein to promote anabolism (goal for anabolism is +2-4g of nitrogen a day more). So, that low end we are aiming for is 2g of nitrogen: 2N (6.25g of protein/1g of nitrogen) = 12.5g of protein needed to put the patient in positive nitrogen balance. Fifth, we want to try to promote anabolism, so we have to add the amount of protein that puts the patient at nitrogen balance to the amount of protein that puts the patient in positive nitrogen balance, and add the sum of those two to the amount of protein the patient is taking in (the 94g). Hence the new protein goal is 94g + 12.5g + 12.5g = 119g of protein/day or approximately 120g of protein per day.

Remember: even though you prescribed 100g of protein a day, the patient only actually got 94g. So, that’s why you use 94g in these calculations.

         A valid 24-hour urine collection can be difficult to collect

       Conversion factor of UUN to total nitrogen excretion may not be accurate in certain conditions: burns, major wounds, diarrhea, vomiting

       Factor of 0.85 converts UUN to TUN

       Assumes that 85% of urinary nitrogen is from urea

       Other nitrogen sources in urine= ammonia, proteins

       Conditions that alter or increase ammonia excretion will lead to underestimation

       Ex if Adam had liver disease and ammonia excretion was higher/ UUN only 75%

◦       UUN = 13   (13/0.75) = 17 (vs 15)

       Diminished renal function alters results

  For the most part you are addressing whether the patient is renal insufficient or dehydrated. BUN:Cre ratio, if high BUN and Cre is normal, then it's usually dehydration. If the BUN and Cre are high, it's often renal failure.

 LABS:

K+, Cr, and Phosphate are often looked at when assessing kidney function. K+, Mg2+, phosphate are often looked at together as well

Refeeding syndrome (hemodilution, hemodynamics) is indicated by labs. Lab error (e.g. blood that has been sitting out too long, things degrade), stress impacts labs, components of the blood (e.g. serum iron) need to be looked at with other portions of bloodwork. Disease states affect labs. High blood glucose can begin to displace sodium, causing sodium to appear low (false low result), like in diabetic ketoacidosis.

 •       Think about which labs are affected by which organ system

•       Lungs: chloride, acetate

•       Kidneys: BUN, creatinine, potassium, phosphorus, albumin, calcium

•       Heart: Sodium, BUN (volume status)

•       Pancreas: Blood glucose, serum lipase

•       Liver: Liver function tests

•       Liver disease: colloidal pressure AKA oncotic pressure. With liver disease, you’re not going to make as much visceral proteins (like albumin), which hang onto the water portion of the blood. If albumin is not hanging on, it will start to seep out and accumulate in different places (third spacing).

•       Pleural effusions are seen commonly in malignancy. Ascites from cancer, for example. Just because patient doesn't have liver disease doesn't mean they won't have issues with fluid. Extra fluid creates a dilution efffect (causing sodium and albumin, calcium, etc. appear low. If you take those labs at face value, you can be thrown off.

Liver disease: colloidal pressure AKA oncotic pressure. With liver disease, you’re not going to make as much visceral proteins (like albumin), which hang onto the water portion of the blood. If albumin is not hanging on, it will start to seep out and accumulate in different places (third spacing).

Pleural effusions are seen commonly in malignancy. Ascites from cancer, for example. Just because patient doesn't have liver disease doesn't mean they won't have issues with fluid. Extra fluid creates a dilution effect (causing sodium and albumin, calcium, etc. appear low. If you take those labs at face value, you can be thrown off.

 Serum sodium doesn't really relate to dietary sodium. Serum sodium is a marker of fluid status, because salt is like a sponge and pulls in a lot of fluid. So, if sodium is really low, often times there’s a fluid issue going on. High sodium indicates a fluid deficit.

 •       Potassium: 3.4– 5.1 mmol/L

•       Magnesium: 1.7 – 2.6 mg/dL

•       Low magnesium can make it difficult to successfully replete potassium and phosphorus (SO YOU WANT TO MAKE SURE MAGNESIUM IS NORMAL)

•       Phosphorus: 2.4 – 4.3 mg/dL

Story: Patient with a phosphorus of 7 starting nutrition at a slow rate, but then his team gave him a bunch of dextrose-containing fluids to correct a sodium issue, and his phosphorus then dipped to a 2! This results from massive refeeding. The trends in your potassium, magnesium, phosphorus are important. What essentially happened was that the glucose (dextrose) activated insulin, and insulin activation caused a massive shift intracellularly of phosphorus, leading to lower levels of phosphorus in the blood. When not eating much, your cells aren’t taking in magnesium and phosphorus, etc. So, again, sugar stimulates intracellular shift because insulin will activate when sugar is reintroduced, leading to even lower blood levels of minerals. Your heart won’t have enough potassium to beat properly, your lungs won’t have enough phosphorus to breathe well. Certain diuretics can lead to potassium deficiency, E.g. thiamin follows potassium (Wernicke's Encephalopathy), certain diuretics that are potassium wasting come with a risk of thiamin deficiency. Can fix this by prophylactically give thiamin in anticipation of potassium drop.

CONSEQUENCES OF REPLETING TOO QUICKLY

•       Low potassium: cardiac arrhythmia, cardiac arrest

•       Low magnesium: seizure, coma

•       Low phosphorus: respiratory distress, difficulty breathing/getting off mechanical ventilation

 Patients who are at risk for refeeding syndrome can have a number of different conditions to begin with:

•       Anorexia nervosa

•       Chronic alcoholism

•       Cancer

•       Post-surgery (NPO for many days pre- and post-op)

•       Elderly (poor dentition, reduced thirst/taste sensation)

•       Uncontrolled diabetes mellitus (electrolyte abnormalities, polyuria)

•       Critically ill and unfed for >7 days

•       Inflammatory bowel disease, chronic pancreatitis, short bowel syndrome

•       Cystic fibrosis

•       Long-term antacid use (phosphorus levels are often low 2/2 magnesium and aluminum salts in the medications)

•       Long term diuretic use (potassium-wasting) such as with CHF

•       Patients who are vomiting frequently

Patients with poor blood levels at baseline (K/Mg/P) will be at risk of intracellular shifts and thus lower blood lab values. Patients with SBD have reduced absorptive capacity, for example, and are at risk for refeeding syndrome.

•       When a patient is experiencing hyperkalemia (K+ > 5.1 mmol/L), there are a number of treatments a Team may utilize

•       50% Dextrose ampule + Insulin

•       Calcium Gluconate

•       Kayexalate or Lokelma

•       Why would we use these medications? (insulin will stimulate intracellular K+ shift, Lokelma and Kayexalate bind potassium)

Giving dextrose and insulin mimics refeeding. So, you are pulling potassium out of the blood and giving it to the cells.

Giving dextrose and insulin mimics refeeding. So, you are pulling potassium out of the blood and giving it to the cells. With renal patients who are often in a hyperkalemic state, kayexalate and lokelma will stop potassium absorption in GI tract. When someone’s potassium hits the ceiling, arrhythmia can occur. Calcium is given to offset that. If a pt is hyperkalemic and EKG changes are seen, patient is given 2g of calcium. Calcium gluconate is the preferred IV administration for hypocalcemia (Severe symptomatic hypocalcemia should be corrected promptly with IV administration of calcium gluconate over 10 minutes to control symptoms. Calcium gluconate is the preferred salt for peripheral venous administration to avoid extravasation—leakage of liquid into surrounding tissue.)

 Specialized labs: Liver function tests give you enzymes (alanine aminotransferase and aspartate aminotransferase, ALT and AST) and you are also given bilirubin as s measure of liver function, as bilirubin is a waste product of heme metabolism. When liver is not functioning well, bilirubin won't be cleared well. At that point, liver is also not good at clearing minerals such as copper and manganese.

 Liver function tests give you enzymes (alanine aminotransferase and aspartate aminotransferase, ALT and AST) and you are also given bilirubin as s measure of liver function, as bilirubin is a waste product of heme metabolism. When liver is not functioning well, bilirubin won't be cleared well. At that point, liver is also not good at clearing minerals such as copper and manganese.

When T. bili is >5 mg/dL, give PO multivitamin without minerals, or remove copper and manganese from your TPN (total parenteral nutrition) solution

If patient is eating, give them a multivitamin without minerals. If patient is on TPN, remove copper and manganese, as toxicity of these can risk brain damage.

Blood and iron studies: Hemoglobin is the last thing to change. Look at ferritin as an earlier sign. Hematocrit can respond to anemia, but also to an overflow of other blood cells. Professor Trussler works with blood in the heme oncology setting. White blood cells in certain type of malignancies (e.g. leukemia) are elevated. Blood smear can count white blood cells and immature white blood cells (blasts). High blasts signals that something is wrong in bone marrow and they’re pumping a lot of immature white blood cells out. Also, immature blasts are a measure of whether someone’s chemotherapy has been effective. Treatment decisions can be made on this.

Absolute number of neutrophils can be used to determine treatment decisions. Low neutrophil count can be used as a guideline for a neutropenic (low bacteria) diet.

A1C: 3-month average blood glucose. When someone is acutely ill, you can see high glucose in the blood, but this is not diabetes, it’s “stress hyperglycemia” (due to injury). But if this is prolonged, an A1C can help you see if they have undiagnosed prediabetes. A1C is useful for newly diagnosed diabetic patients.

Lipase: You shouldn't be seeing a lot of lipase in the bloodstream, as this indicates pancreatic damage (e.g. pancreatitis)

 Vitamin and mineral labs get expensive, so you don't want to be checking EVERYTHING for every situation. There are some vitamins and minerals where a serum lab isn't going to be helpful. E.g. pyridoxine (B6), Per the American Society of Parenteral and Enteral Nutrition (A.S.P.E.N.), you need serum B6, 24-urinary B6, erythrocyte AST, and erythrocyte ALT to assess sufficiency of B6.

Common vitamin labs:

·      Someone who is having trouble absorbing fat will be at risk for vitamin A deficiency. Vitamin A is key to skin integrity and building (a pressure injury/injuries not healing well may indicate vitamin A deficiency), with substance use disorder deficiency comes up because you’re generating a lot of free radical damage from substance use disorders and the vitamin A is getting used up for that. Vitamin A is protein bound (RBP), so you can look at C-reactive protein in combination with this, because vitamin A may look low when it's not (falsely low result).

·      B12 is worth looking at, esp. for vegans, vegetarians, elderly, heavy alcohol or substance users, and patients with IBD.

·      Vitamin C builds collagen matrix for skin, thus wounds could cause a vitamin C deficiency in wound patients. Dialysis causes water loss, so you can lose vitamin C. COVID-19 may cause a vitamin C deficiency (the antioxidant vitamin is getting used up).

·      Check vitamin D, after it's activated by the kidneys a second time, that active form doesn't last very long, so it may not give you a good result. Vitamin D labs are good to check for elderly patients who don’t synthesize enough vitamin D, and for kidney injury patients because their kidneys aren’t activating as much vitamin D. Checking vitamin D for oncology patients is also great, because they may have some complications in certain cancer treatments. COVID-19 appears to be affecting vitamin D levels.

·      Vitamin E is good to check in a patient who is malabsorbing fat. If you think someone is malabsorbing, the team can do more work up.

 Less common vitamin labs:

If the vitamin is water soluble, there’s less risk of toxicity, so you can give it prophylactically. For example, folate costs about $1, so it can be given for 3 days prophylactically.

B1 (thiamin) is given prophylactically if you think the patient is deficient. At Brigham and Women’s, if you anticipate that someone might refeed, you give them thiamin for the first few days that they’re getting nutrition support to anticipate that shift with potassium.

Professor T doesn’t usually check vitamin K often, because gut microbiota make vitamin K. Prothrombin (PT-INR, a marker of blood clotting) is a better indicator of vitamin K sufficiency because the clotting factors in your blood need vitamin K to work. If you were truly functionally deficient, you would have trouble clotting.

Common mineral labs

Both copper and ceruloplasmin must be low in order to diagnose a true copper deficiency. Bariatric patients tend to be low, esp. in Roux-en-Y gastric bypass patients, as the surgery is bypassing some of the areas where copper is absorbed. Wouldn't normally suspect a copper deficiency unless there's some sort of malabsorptive process occurring.

Zinc deficiency is caused by (and can also cause) diarrhea. If you have someone with diarrhea that isn’t resolving, it could be due to zinc deficiency, and also zinc could be causing the diarrhea. Zinc is lower in stressed state. If a patient is borderline deficient and their CRP is very high, you may want to hold off on repleting zinc, and then check zinc levels again.

Selenium, like zinc, decreases when someone has diarrhea, but can also cause diarrhea as a side effect of deficiency. Selenium will be low in substance use disorder patients, as it participates in antioxidant functioning (where antioxidants get used up).

 Less common mineral labs:

Manganese: No good lab test to measure for this. If worried patient is getting too much, try to just remove it. E.g. taking manganese out of total parenteral nutrition, or giving a supplement that doesn’t have manganese. Manganese toxicity can cause brain damage

Chromium: No real lab measure for chromium, either, but people on long term TPN might develop this deficiency. Sometimes chromium is given prophylactically. People who are diabetic can be low in chromium, but it is difficult to figure out because you can’t check this mineral.

Specialty Lab

•       Fecal Calprotectin

•       Marker of inflammatory bowel disease

•       Protein released by immune cells (neutrophils) at sites of inflammation in the GI tract, which is then excreted in the stool

•       Low level (10-50 mcg/mg): likely IBS or viral infection

Abstract

Background: Despite its importance in understanding acid-base pathophysiology, many physicians do not comprehend the concept of the strong anion gap (SIG), the core of the Stewart acid-base approach. The quantitative difference between the anion gap and the strong ion gap is not established. This paper will give insight into this difference over a variety of conditions Methods. The empiric difference between the SIG and the albumin-corrected anion gap (AGc) was calculated at a wide range of albumin, phosphorus and pH levels.

Results: At an albumin level of 1-3 g/dl and pH from 6.9-7.3, the contribution difference of albumin between the AGc and the SIG will be maximally -0.97 to 0.51mEq/L. In metabolic alkalosis and hypoalbuminaemia, the AGc differs less than 2mEq/L from the SIG. The calculated contribution of phosphorus is higher in the SIG with phosphorus levels >2mmol/L and can be accounted for in the anion gap with the conversion factor 1.76* [phosphorus, in mmol/L].

Conclusion: The SIG and the AGc are nearly identical across a wide range of values, particularly when albumin and phosphorus levels are low. The anion gap will be more precise and incorporate the major components of the SIG using the equation: [Na+]-[Cl-]-[HCO3-]-2.5* [albumin, in g/dL] - 1.76* [phosphorus, in mmol/L], with an arbitrarily set reference range of 1±5mEq/L.

Keywords: Acid-base; Anion gap; Strong anion gap; Stewart

Abbreviations: AGc: Corrected Anion Gap; AlbSt: Albumin Measured By The Stewart Formula; Pst : Phosphate Measured with the Stewart Formula;AGa+p : AG Corrected for Albumin and Phosphorus

Introduction

For more than 40 years clinicians have used the anion gap (AG) as a major tool to evaluate acid-base disorders. A positive value of the AG suggests a possible organic acidosis due to endogenous acids or the intake of exogenous acids [1]. Although the concept of the AG was described in 1936 by James Gamble [2]. it did not gain widespread recognition by physicians until the 1970s after the introduction of auto analyzers and the rapid availability of multiple analytes. According to Gamble, electrical neutrality in solution demands that the sum of the cations is equal to the sum of the anions, also represented in a Gamblegram (Figure 1). Sodium, chloride, bicarbonate and albumin are quantitatively the major ions in the extracellular fluid compartment and are therefore used to calculate the anion gap. A true "ion gap" does not exist in vivo which makes the anion gap a fundamental tool to evaluate acid-base disorders [1]. In 1978 Peter Stewart challenged the traditional bicarbonate- based approach, by reasoning that his approach offered both a mechanistic explanation and provided the tool to make a more accurate diagnosis [3]. The core of the Stewart approach is the strong anion gap (SIG): Equation 1.

[Na+] + [K+] + [Ca2+] + [Mg2+]-[Cl-]-[lactate-]-12.2xpC02/ (10'pH)-10x[albumin]x0.123xpH-0.631)-[PO4- in mmol/ L]x(0.309xpH-0.469)= +0mEq/L

This complex formula quantitatively accounts for the contribution of weak acids to the electrical charge equilibrium in plasma [3]. On first glance there is a substantial difference from the AG equation: Equation 2.

[Na+]-[Cl-]-[HC03-]=+10mEq/L

Though the SIG gives a wider-ranging picture of the ion balance than the AG, controversial opinions about its real value remain and several differences are observed between the SIG and the AG:

[Na+]-[Cl-]-[HC03-]-10x[albumin]x(0.12 3xpH-0.631)- [P04]x(0.309 pH-0.469)=+0mEq/L.

Methods

The quantitative difference between the SIG and the AGc was calculated at a wide range of albumin (from 1 to 5 g/L), phosphorus (from 0.5to4mmol/L) and pH levels (from 6.9to7.6) with otherwise standard parameters. For example, with an albumin of 4 g/dl and a pH of 6.9, the albumin effect on the anion gap will be 10mmol/L regardless of the pH. The SIG will change using the formula 10x[albumin]x(0.123xpH-0.631), by 8.71mmol/L. Thus, the Δ AlbSt-10=8.71-10=-1.29mmol/L. Similarly, with a phosphorus of 1mmol/L and a pH of 6.9, the PSt=[P04-]x(0.309xpH-0.469)=1.66mEq/l difference with the AG.

Results

At an albumin level of 1-3 g/dl and a pH from 6.9-7.3, the contribution difference of albumin in the AGc and the SIG will be maximally -0.97 to 0.51mEq/L, suggesting little difference between the two methods (Table 1). In metabolic alkalosis and hypoalbuminaemia, once again the AGc differs less than 2mEq/L from the SIG. Incorporation of phosphorus in the SIG is significant and there is a linear relationship of the serum phosphorus and the ionic contribution in the SIG (supplemental data). This effect will therefore be more notable at higher phosphorus levels (Table 1).

AlbSt = albumin concentration calculated by the Stewart method: 10 * [albumin] * (0.123 * pH - 0.631).

PSt = phosphorus concentration calculated by the Stewart method: [PO4- in mmol/L] * (0.309 * pH - 0.469).

Δ Alba - albumin at a certain level calculated by the Stewart method minus the albumin concentration  adjusted for the corrected anion gap method (2.5 g/dL for each g/dL change). Example: with albumin = 4 g/dl at a pH = 6.9 the albumin effect on the anion gap will be 10 mmol/L (regardless of the pH in the anion gap concept). The SIG will change using the formula 10 * [albumin] * (0.123 * pH - 0.631), by 8.71 mmol/L.

Δ AlbSt - 10 = 8.71 - 10 = -1.29 mmol/L.

Δ PSt phosphorus concentration at a certain level calculated by the Stewart method minus the phosphorus. Example: If the phosphorus is 1 mmol/L and the pH is 6.9, the change in SIG will be 1.66 mmol/L using the formula: {[PO4-] * (0.309 * pH - 0.469)}. The pH adjusted level A

PSt - 1 = 1.66 - 1 = 0.66 mmol/L.

⊗PSt-1 = 1.66 - 1 = 0.66 mmol/L.

aReference range albumin (3.5-5.5 g/dL)

bReference value phosphorus: 0.97-1.45 mmol/L

Discussion

Body fluid compartments have varying concentrations of non-volatile weak acids, with albumin and inorganic phosphorus the primary components in plasma [3]. The anion gap is used to evaluate metabolic acidosis and is calculated as follows:

[Na+]-[Cl-]-[HC03-]

Because of the narrow extracellular concentration, K+ is often omitted from the calculation. To be more precise, one should correct the anion gap for hypoalbuminemia. To appreciate the relevance of this correction one can consider a healthy individual with the following serum values:

[Na+]=140mEq/L, [Cl-] = 106mEq/L, [HC032-]=24mEq/L.

The AG=10mEq/L, representing primarily albumin. The correction factor for albumin is 2.3-2.5 * [albumin], in g/dL [1]. The albumin corrected AG (AGa) equation can therefore be written as: Equation 4.

[Na+]-[Cl-]-[HC032-]-2.5 [albumin, in g/dL]=0+5mEq/L.

This equation gives a better understanding of the principle that there is no actual "gap" between the positive and negative ions and likewise, the "AG" should be zero in-vivo. However, comparing this formula with the SIG, one will observe that a major difference is the inclusion of phosphorus in the SIG and that albumin and phosphorus are both adjusted for changes in pH. The question is therefore if one should include phosphorus as well in the AG.

Albumin

Hypoalbuminemia is common in patients with acid-base disorders. With an albumin of 1-3 g/dl, the contribution difference of albumin between the AG and the SIG will be maximally -0.97 to 1.6mEq/L  regardless of pH (Table 1).Therefore, the pH correction of albumin used in the SIG formula is irrelevant in the evaluation of metabolic acidosis, as long as the AG is adjusted for albumin.

Phosphorus

When phosphorus levels are normal or reduced, there is little contribution (<2mmol/L) to the AG (Table 1). If phosphorus levels are elevated, as in renal failure, the ionic contribution, however, becomes more significant. Suppose we have a patient with renal failure and the following plasma electrolytes: [Na+]=140mEq/L, [Cl-]=106mEq/L, [HC032-]=24mEq/L, albumin 4g/dL, phosphorus of 6mmol/L (reference value 0.97-1.45 mmol/L), and a pH of 7.0. The anion gap corrected for albumin will be zero. When using equation 3 the SIG will be 6.78mEq/L due to the high phosphorus level. The linear relationship of serum phosphorus and the ionic contribution in the SIG can be incorporated in the traditional AG formula (Figure 2). The SIG can thus be replaced by the following adjustment to the AG formula: Equation 5.

AG corrected for albumin and phosphorus (AGa+p)=[Na+]-[Cl- ]-[HCO3-]-2.5[albumin, in g/dL]- 1.76 [phosphorus, in mmol/L] and as the median phosphorus level is about 1.2, the reference value will be about -2+5mEq/L. A similar equation has been proposed by Kellum et al. [4].

Conclusion

In conclusion, the SIG and AG are almost identical in a variety of physiological acid-base conditions. When phosphorus levels are elevated, one can use the less complex AGa+p equation as an accurate representation of the SIG. To have a better understanding of the pathophysiology and to be more accurate, the anion gap, or perhaps a more logical term, "the ion gap" should be written as equation 5 to become almost identical to the SIG.

Acknowledgment

We are indebted to Jan Williem boldingh for malimg Figure 1.

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Anion Gap

[Na] - ([Bicarb] + [Cl])

[Na] - [Bicarb] - [Cl]

Osmolal gap should be calculated in a patient with anion gap metabolic acidosis and suspected ingestion.

Osmolal gap = Measured serum osmolality - Calculated serum osmolality

Calculated serum osmolality

Abstract

The serum anion gap, calculated from the electrolytes measured in the chemical laboratory, is defined as the sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration. This entity is used in the detection and analysis of acid-base disorders, assessment of quality control in the chemical laboratory, and detection of such disorders as multiple myeloma, bromide intoxication, and lithium intoxication. The normal value can vary widely, reflecting both differences in the methods that are used to measure its constituents and substantial interindividual variability. Low values most commonly indicate laboratory error or hypoalbuminemia but can denote the presence of a paraproteinemia or intoxication with lithium, bromide, or iodide. Elevated values most commonly indicate metabolic acidosis but can reflect laboratory error, metabolic alkalosis, hyperphosphatemia, or paraproteinemia. Metabolic acidosis can be divided into high anion and normal anion gap varieties, which can be present alone or concurrently. A presumed 1:1 stoichiometry between change in the serum anion gap (ΔAG) and change in the serum bicarbonate concentration (ΔHCO3−) has been used to uncover the concurrence of mixed metabolic acid-base disorders in patients with high anion gap acidosis. However, recent studies indicate variability in the ΔAG/ΔHCO3− in this disorder. This observation undercuts the ability to use this ratio alone to detect complex acid-base disorders, thus emphasizing the need to consider additional information to obtain the appropriate diagnosis. Despite these caveats, calculation of the serum anion gap remains an inexpensive and effective tool that aids detection of various acid-base disorders, hematologic malignancies, and intoxications.

The serum or plasma anion gap is an entity that is calculated from the electrolytes that are obtained in the chemical laboratory (1–3). Although most commonly used in the differential diagnosis of acid-base disorders, it also has been used to assess quality control in the chemical laboratory (1) and to diagnose paraproteinemias (4,5) and intoxications with lithium (6), bromide (7), or iodide (8). For many years, the electrolytes that were required to calculate the serum anion gap were included in electrolyte panels that were requested by physicians. However, because of the emphasis on cost containment, physicians in many institutions now specifically must request that the relevant electrolytes be measured, a situation that reduces the availability of the serum anion gap. Therefore, it is timely and worthwhile to reassess the value of the serum anion gap in clinical medicine by highlighting the factors that affect its calculation, reviewing the situations in which it is most useful, and specifying its limitations as a diagnostic tool.