**12. Reduced anion gap**

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 anion gap [52].

## **13. Normal anion gap**

Measuring anion gap is a routine for evaluating acidosis, and normal anion gap is sometimes misleading. As we know, the increase in anion gap is usual in metabolic acidosis. And acidosis is due to acid retention or ingestion. Normal anion gap acidosis is due to loss of HCO3 <sup>−</sup> from the body. Hyperchloremic normal anion gap acidosis is characterized by acidosis with excess chloride ions [54]. Here, the low HCO3 level is a characteristic feature. Reduced negatively charged bicarbonate is compensated by the negatively charged chloride movement into the extracellular space, and normal anion gap is maintained. The causes of gastrointestinal and renal loss of bicarbonate are diarrhea, ureteral diversions, pancreatic and biliary fistulas, toluene ingestion, acetazolamide, ifosfamide, topiramite, tenofovir, renal tubular acidosis. These are the causes of normal anion gap acidosis. Rapid infusion of 0.9% normal saline can also cause hyperchloremic metabolic acidosis [55]. If the blood anion gap is normal, but there is acidosis, then the urinary anion gap Eq. (6) is calculated [12].

$$\begin{array}{c} \text{[Na}^\*\text{]} \text{ + [K}^\*\text{]} - \text{[Cl}^-\text{]} \end{array} \tag{6}$$

**193**

**Author details**

Dhaka, Bangladesh

Md. Masudul Hassan1,2,3

1 Bangladesh College of Physicians and Surgeons, Dhaka, Bangladesh

3 DHCRL and IB Hospital, Dhaka, Bangladesh

provided the original work is properly cited.

\*Address all correspondence to: masud292@yahoo.com

2 Department of Rheumatology, Bangabandhu Sheikh Mujib Medical University,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Acidosis and Anion Gap*

erly treated.

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

Following anion gap measurement accordingly history of drug, toxins and diseases need to be evaluated for managing the exact pathology thus acidosis will be prop-

At normal blood pH 7.4 plasma proteins are mostly anionic. It has been estimated that anion gap decreases by 2.5 mEq/L for every 10 gm/L drop of serum albumin [36, 37]. Several studies had observed that 2–2.5 times changes in albumin influences in anion gap changes [58]. Albumin contributes a greater part of the normal anion gap [46]. Phosphate and lactate contribute some anion gap as well [59]. Consideration of all of these contributors are important in explaining changes in anion gap. Calculation of anion gap is crucial in critically ill patients. Anion gap should be adjusted for Eq. (7)

+ 0.5 × phosphate mg/dl} − {lactate mmol/L} (7)

**15. Albumin, phosphate, lactate and corrected anion gap**

albumin, phosphate and lactate with the following equation [59].

Anion gap = {(Na) + (K) − (Cl) − (HCO3)} − {2 × albumin g/dl

The urinary anion gap is negative in diarrhea, sodium infusion and proximal renal tubular acidosis. Whereas, positive urinary anion gap is found in both type 1 and type 4 renal tubular acidosis. Renal tubular acidosis is sometimes the only presenting feature of many chronic diseases and conditions associated with polyclonal gummopathies.

## **14. Metabolic acidosis and anion gap**

Metabolic acidosis results from gain of anions and loss of cations. Potassium chloride, hydrogen chloride, sodium chloride, arginine hydrochloride, calcium chloride, ammonium chloride, lysine hydrochloride can cause hyperchloremia and increase anion gap. Hyperphosphatemia increases the anion gap. But renal tubular acidosis [33], amiloride and triamterene cause a non anion gap hyperchloraemic acidosis and hyperkalemia due to impaired bicarbonate production.

Anion gap should be measured for all types of metabolic acidosis. High anion gap metabolic acidosis is a subtype of non-respiratory acidosis. Mnemonics were used for remembering the causes of high gap metabolic acidosis such as KUSMALE (Ketoacidosis, Uraemia, Salicylate poisoning, Methanol, ParAldehyde, Lactate, Ethylene glycol) and MUD PILES (Methanol, Metformin uremia, Diabetic ketoacidosis, Paraldehydes, iron, isoniazid, Lactate, ethylene glycol, Salicylates and starvation). As paraldehyde induced acidosis is extremely rare and recently three anion gap generating organic acid has been recognized. They are Short bowel syndrome producing D-lactic acid, chronic paracetamol use induced 5-oxoproline (or pyroglutamic acid) especially in malnourished woman and high dose propylene glycol (used in lorazepum, phenobarbital) infusions generate acidosis. Also, Iron and Isoniazid can cause lactic acidosis. So, GOLD MARK is a new acronym for metabolic acidosis [Glycols (ethylene and propylene), Oxyproline, L-lactate, D-lactate, Methanol, Aspirin, Renal failure, Ketoacidosis] [56]. Metabolic acidosis also caused by renal bicarbonate loss in type 2 renal tubular acidosis, renal dysfunction in type 4 renal tubular acidosis, type 1 renal tubular acidosis and ingestion of ammonium chloride [31]. Acute rheumatism causes lactate induced acidosis also [57]. Symptomatic correction of acidosis will not eliminate the problem. If the clinical features suggest acidosis, then it should be assessed for anion gap as well.

*New Insights into Metabolic Syndrome*

acidosis is due to loss of HCO3

Eq. (6) is calculated [12].

clonal gummopathies.

**14. Metabolic acidosis and anion gap**

Measuring anion gap is a routine for evaluating acidosis, and normal anion gap is sometimes misleading. As we know, the increase in anion gap is usual in metabolic acidosis. And acidosis is due to acid retention or ingestion. Normal anion gap

acidosis is characterized by acidosis with excess chloride ions [54]. Here, the low HCO3 level is a characteristic feature. Reduced negatively charged bicarbonate is compensated by the negatively charged chloride movement into the extracellular space, and normal anion gap is maintained. The causes of gastrointestinal and renal loss of bicarbonate are diarrhea, ureteral diversions, pancreatic and biliary fistulas, toluene ingestion, acetazolamide, ifosfamide, topiramite, tenofovir, renal tubular acidosis. These are the causes of normal anion gap acidosis. Rapid infusion of 0.9% normal saline can also cause hyperchloremic metabolic acidosis [55]. If the blood anion gap is normal, but there is acidosis, then the urinary anion gap

[Na<sup>+</sup>

acidosis and hyperkalemia due to impaired bicarbonate production.

] + [K<sup>+</sup>

The urinary anion gap is negative in diarrhea, sodium infusion and proximal renal tubular acidosis. Whereas, positive urinary anion gap is found in both type 1 and type 4 renal tubular acidosis. Renal tubular acidosis is sometimes the only presenting feature of many chronic diseases and conditions associated with poly-

Metabolic acidosis results from gain of anions and loss of cations. Potassium chloride, hydrogen chloride, sodium chloride, arginine hydrochloride, calcium chloride, ammonium chloride, lysine hydrochloride can cause hyperchloremia and increase anion gap. Hyperphosphatemia increases the anion gap. But renal tubular acidosis [33], amiloride and triamterene cause a non anion gap hyperchloraemic

Anion gap should be measured for all types of metabolic acidosis. High anion gap metabolic acidosis is a subtype of non-respiratory acidosis. Mnemonics were used for remembering the causes of high gap metabolic acidosis such as KUSMALE (Ketoacidosis, Uraemia, Salicylate poisoning, Methanol, ParAldehyde, Lactate, Ethylene glycol) and MUD PILES (Methanol, Metformin uremia, Diabetic ketoacidosis, Paraldehydes, iron, isoniazid, Lactate, ethylene glycol, Salicylates and starvation). As paraldehyde induced acidosis is extremely rare and recently three anion gap generating organic acid has been recognized. They are Short bowel syndrome producing D-lactic acid, chronic paracetamol use induced 5-oxoproline (or pyroglutamic acid) especially in malnourished woman and high dose propylene glycol (used in lorazepum, phenobarbital) infusions generate acidosis. Also, Iron and Isoniazid can cause lactic acidosis. So, GOLD MARK is a new acronym for metabolic acidosis [Glycols (ethylene and propylene), Oxyproline, L-lactate, D-lactate, Methanol, Aspirin, Renal failure, Ketoacidosis] [56]. Metabolic acidosis also caused by renal bicarbonate loss in type 2 renal tubular acidosis, renal dysfunction in type 4 renal tubular acidosis, type 1 renal tubular acidosis and ingestion of ammonium chloride [31]. Acute rheumatism causes lactate induced acidosis also [57]. Symptomatic correction of acidosis will not eliminate the problem. If the clinical features suggest acidosis, then it should be assessed for anion gap as well.

] − [Cl<sup>−</sup>

<sup>−</sup> from the body. Hyperchloremic normal anion gap

] (6)

**13. Normal anion gap**

**192**

Following anion gap measurement accordingly history of drug, toxins and diseases need to be evaluated for managing the exact pathology thus acidosis will be properly treated.
