**9. Anion gap**

In vivo, true ion gap cannot exist. There are many anions and cations in the blood. Blood cations and anions must be equal. Sodium, chloride and bicarbonate have the highest concentrations, and they are calculated for anion gap for their largest variability in different pathologic conditions. Anion gap is the difference between serum sodium ion and bicarbonate plus chloride. There are wide variations in the reported anion gap. Widely accepted anion gap is 8–12 mmol/L [15]. Anion gap is clinically important for assessing acidosis. Normal anion gap (hyperchloremic) acidosis and increased anion gap acidosis [27] are two important types of anion gap acidosis. Common serum cation levels are sodium 138.8 ± 4.56 mmol/L, potassium 4.05 ± 0.21 mmol/L, magnesium 0.98 ± 0.05 mmol/L [ 28] and calcium 2.2–2.7 mmol/L [ 29]. And normal serum anion levels are chloride 97.7 ± 3.42 mmol/L and acetate 0.23 ± 0.04 mmol/L [ 28]. The sum of cations and anions should be equal (Eq. (4)).

$$\begin{aligned} \text{Na}^+ + \text{K}^+ + \text{Mg}^+ + \text{Ca}^+ + \text{Protein}^+ &= \text{Cl}^- + \text{OA}^- + \text{HCO}\_3^- + \text{SO}\_4^{-2} \\ &+ \text{HPO}\_4^{-2}/\text{HPO}\_4^- + \text{Protein}^- \end{aligned} \tag{4}$$

There are other ions which are not commonly measured, are unmeasured anions and cations [30]. Under normal conditions, albumin and phosphate accounts for this anion gap. There are many clinical conditions, where urate, lactate, ketone bodies, sulfate, salicylates, penicillin's, citrate, pyruvate, and acetates are also responsible for increased anion gap [5]. So, anion gap [31] is Eq. (5)

$$\text{Na} - \left(\text{Cl}^{+} + \text{HCO}\_{3}^{-}\right) = \text{UA} - \text{UC} \tag{5}$$

**191**

anion gap [52].

*Acidosis and Anion Gap*

**11. Increased anion gap**

**12. Reduced anion gap**

*DOI: http://dx.doi.org/10.5772/intechopen.91760*

has no hydrogen can cause severe metabolic acidosis [39].

other causes of unmeasured anions [33]. Both lactate and β-hydroxybutyrate are increased in both Gram-positive septiceamia [34] and starvation [35]. Krebs cycle intermediate citrate, isocitrate, malate, α-ketogluterate, succinate and D-lactate are increased in different types of acidosis. Intestinal ischemia and short bowel syndrome cause increase in D-lactate [35]. Plasma proteins are mostly anionic comprising 75% of the unmeasured anion [36–38]. Treatment with Sodium thiosulfate that

It usually indicates acidosis. Increase blood lactate, ketoacidosis, uremia (in advanced renal failure), drugs (salicylate and penicillin), ethylene glycol, methanol are contributor of high anion gap acidosis. But the increase anion gap can be due to laboratory error, hyperphosphatemia [30]. Massive rhabdomyelysis, hippurate, oxalate can also cause increased anion gap acidosis [31]. Diabetes, starvation and alcohol are the most common cause of ketoacidosis. In alcoholic ketoacidosis, primary keto acid is β-hydroxybutyrate. It can be missed in conventional assessment of ketonuria. High anion gap and normal lactate level are characteristics of alcoholic acidosis [40]. Starvation alone can cause high anion gap acidosis [41]. In the third trimester of pregnancy, short period of starvation can cause ketogenesis with a very high anion gap acidosis [42]. Septic shock, hypoxemia, hypovolemic shock, cyanide, mesenteric ischemia, CO poisoning, causes hypoxic type of L-lactic acidosis [43]. Non-hypoxic, L-lactic acidosis develops from seizure, thiamine deficiency, metformin, methanol, ethylene glycol, salicylate, propylene glycol, niacin, isoniazide, iron, propofol, toluene, paraldehyde, non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs [12]. Recurrent 5-oxoprolinuria from inborn errors of metabolism is a rare cause if high anion gap metabolic acidosis [44]. Uremia results from not only reduced ammonia secretion but also reduced filtration of sulfate and phosphate anions, and increases the anion gap [45]. Polyclonal gammopathies are also contributor of increased anion gap [46]. Serum albumin is an important contributor to the anion gap and hypoalbuminemia is a common comorbid condition. That is why, albumin correction is crucial for the anion gap calculation [36, 37]. To explore the cause of the metabolic acidosis anion gap must be corrected for albumin as well as lactate [43]. A high anion gap can

be masked by a concomitant low anion gap results from hypoalbuminemia.

In anion gap calculation, sodium is the only cation that is measured. But, hypercalcemia, hyperkalemia and hypermagnesemia can produce significant decrements in anion gap. So, clinical correlation and correction of such abnormality is important. Plasma proteins comprise two third of the unmeasured anion, and hypoalbuminemia is a common cause for the low anion gap [31, 36, 37]. The reduced anion gap is usually seen in delusional states, hypernatremia, hypoalbuminemia, hypermagnesemia, hypercalcemia, bromide intoxication, hyperviscosity associated diseases etc. [47]. Sometimes it can be due to laboratory error, paraproteinemia [48, 49], or iodide [30, 50], gastrointestinal bicarbonate loss and diarrhea [31]. It has been reported that Lithium carbonate intoxication can also produce low or absent anion gap [51]. Non-sodium containing paraprotein IgG in multiple myeloma increase the unmeasured cations and reduce the anion gap [48, 52, 53]. Hypercalcemia and hypoalbuminemia in paraproteinemia also contribute to low

## **10. Unmeasured anion**

Presence of unmeasured anion in blood is the anion gap and it represents metabolic acidosis [32]. When unmeasured anions like lactate and pyruvate donates proton then that proton is buffered by bicarbonate. And bicarbonate consumption increases the anion gap. The most common causes include lactic acidosis, diabetic ketoacidosis, uremia and acidosis due to drugs and toxins. Methanol, propylene glycol, ethylene glycol, salicylate, and some inborn error of metabolism are

#### *Acidosis and Anion Gap DOI: http://dx.doi.org/10.5772/intechopen.91760*

other causes of unmeasured anions [33]. Both lactate and β-hydroxybutyrate are increased in both Gram-positive septiceamia [34] and starvation [35]. Krebs cycle intermediate citrate, isocitrate, malate, α-ketogluterate, succinate and D-lactate are increased in different types of acidosis. Intestinal ischemia and short bowel syndrome cause increase in D-lactate [35]. Plasma proteins are mostly anionic comprising 75% of the unmeasured anion [36–38]. Treatment with Sodium thiosulfate that has no hydrogen can cause severe metabolic acidosis [39].
