**11. Increased anion gap**

*New Insights into Metabolic Syndrome*

with this weak A<sup>−</sup>, and HCO3+<sup>−</sup>, H+

from an increase in [Na+

that cause a wide anion gap.

anions should be equal (Eq. (4)).

**10. Unmeasured anion**

Na<sup>+</sup> + K<sup>+</sup> + Mg<sup>+</sup> + Ca<sup>+</sup> + Protein<sup>+</sup>

**9. Anion gap**

A<sup>−</sup> Resembles weak anions, that vary with pH. Strong ion difference is filled

<sup>2</sup><sup>−</sup> are also present in minute amount,

, OH<sup>−</sup>, CO3

but are less important. There are many unmeasured anions accounts for ion difference. For electrical neutrality, strong ion difference and the total charge of weak ions must be equal [26]. Normal SID is dominated by sodium and chloride. But other negligible, but measurable ions are present there. Here narrowing of SID

acidifying effect. From the ionic basis metabolic acid base disturbances are about four major types [25]: (1) The water effect, and it is produced by dilutional effect on SID. Free water intake and intravenous infusion can produce it. (2) The chloride effect is caused by chloride change, and administration of normal saline is the common cause. (3) The protein effect is produced by a change in albumin concentration. (4) There are other factors, and those are influenced by unmeasured anions,

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

responsible for increased anion gap [5]. So, anion gap [31] is Eq. (5)

Na − (Cl<sup>+</sup> + HCO3

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

= Cl<sup>−</sup> + OA<sup>−</sup> + HCO3

−2/ HPO4

+ HPO4

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

−

<sup>−</sup> + SO4 −2

) = UA − UC (5)

<sup>−</sup> + Protein<sup>−</sup> (4)

] has alkalizing effect, whereas an increase in [Cl<sup>−</sup>] has

**190**

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.
