Biochemistry, Anion Gap


Article Author:
Devansh Pandey


Article Editor:
Sandeep Sharma


Editors In Chief:
Rhonda Coffman
Lindsay Iverson
Heather Templin


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
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Radia Jamil
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Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
4/6/2019 8:57:01 PM

Introduction

Using the results of the comprehensive metabolic panel (CMP), the anion gap is the difference between measured cations (positively charged ions like Na+ and K+) and measured anions (negatively charged ions like Cl- and HCO3-). There are three types: serum, plasma, and urine anion gaps. The most common application of the anion gap is classifying cases of metabolic acidosis, states of lower than normal blood pH. Specifically, classifying into either those that do and those that do not have unmeasured anions in the plasma. The human body is electrically neutral; therefore, in reality, does not have a true anion gap. The calculation then finds utility in exposing variations in that balance. However, changes in albumin and bicarbonate concentrations warrant specific attention.[1][2]

Fundamentals

In essence, the anion gap is a mathematical calculation that provides practitioners with the foresight to plan for managing current problems associated with acid-base balance, fluids, and electrolytes.

For reference, a normal anion gap depends on the concentration of phosphate and albumin in the serum and ranges from 4 to 12 mmol/L. An increased or normal anion gap metabolic acidosis is typically due to excess acid and/or decreased base. A reduction in the anion gap is most commonly due to decreased albumin concentration as albumin is the primary unmeasured anion.

To best understand the concept of anion gap, let us revisit the law of electrochemical neutrality. This law states that for any given solution, the net charge after accounting for all cations (positive ions) and anions (negative ions) should arrive at zero. However, at face value, the subtraction between the measured cations and measured anions of the blood does not yield a zero; the 4 to 12 mmol/L range for “normal anion gap.” However, this does not reflect an integral problem in the mathematical derivations, but rather its paramount utility. The resulting positive number in a healthy, asymptomatic patient is a result of the formula accounting only for measured cations and anions, leaving uncalculated cations and uncalculated anions to reach the zero value.

As an example, an anion gap of 8 means after accounting for measured ions (Na+, Cl-, HCO3-, and depending on your institution, K+) we have a net positive charge of 8. However, this gets neutralized by unmeasured anions such as albumin, phosphorus, and miscellaneous proteins. Thus, one can see if the anion gap increased or decreased out of the 4 to 12 mmol/L range, one can expect tangible derangements in measured cations and anions vs. theoretical derangements in their uncalculated counterparts.

Calculation relies on measuring specific cations, Na+ and K+ and specific anions, Cl- and HCO3-. The equation is as follows: (Na+ + K+) – (Cl- + HCO3-) = Anion Gap.

The anion gap formula can be manipulated to expose the presence of unmeasured cations and anions as shown below.

([Na+] + [K+] + [UC]) = ([Cl-] + [HCO3-] + [UA])

Rearrangement shows:

([Na+] +[K+]) – ([Cl-] + [HCO3-]) = [UA] – [UC]

Anion Gap = UA – UC

From this manipulation, a health care practitioner or researcher can see that the 4 to 12 mmol/L range of the anion gap is precisely equal to the difference between the unmeasured anions and cations.[3][4]

Function

The anion gap is used to identify errors in the measurement of electrolytes (sodium, chloride, bicarbonate, and potassium most notably), detect paraproteins (IgG for example), and evaluate for suspected acid-base disorders – the latter being the most common and essential use.

Pathophysiology

General pathophysiology of anion gap revolves around derangements in concentrations of cations and anions. In terms of metabolic acidosis, no matter the cause, the inciting event involves a reduction in bicarbonate concentration. This reduction can be due to increased use as a buffer of abnormal acids, decreased production, or increased loss from the body. However, the law of electrochemical neutrality is never breached, so either chloride concentration increases in tandem, or, unmeasured anions increase. If it is chloride, one would have a normal anion gap metabolic acidosis because it is a measured anion.[3] However, if it is unmeasured anions, it would be reflected as an increased anion gap metabolic acidosis.

Two of the most common and notable causes of increased anion gap metabolic acidosis

High anion gap metabolic acidosis (HAGMA) conditions include diabetic ketoacidosis (DKA) and salicylate poisoning.[5] Descriptions of their pathophysiology are below.

In DKA, the patient presents with rapid onset of vomiting, abdominal pain, increased urination, confusion, and in some cases, fruity odor to the breath. At the cellular level, the foundational error is a lack of insulin in the body. Decreased insulin and increased glucagon cause the liver to release glucose via glycogenolysis and gluconeogenesis. Increased glucose in the blood results in osmotic diuresis, taking water and solutes (sodium and potassium) with it. Most relevant is the lack of insulin leading to lipolysis (release of free fatty acids from adipose tissue). The free fatty acids undergo beta-oxidation in the liver and ketone bodies, acetoacetate and B-hydroxybutyrate form. While they provide energy in the absence of glucose, they have lower pKa, causing blood to turn acidic ultimately resulting in the myriad of symptoms discussed at the beginning.[6][7]

In salicylate poisoning, classic symptoms include ear ringing, nausea, abdominal pain, and hyperventilation. Interestingly, in this case, we find a mixed disorder resulting through three phases:

  1. Through direct respiratory center stimulation, hyperventilation causes respiratory alkalosis and compensation through alkaluria. This phase lasts about 12 hours.
  2. After significant amounts of potassium lost, paradoxical aciduria results.
  3. Eventually, dehydration, hypokalemia, and progressive metabolic acidosis results, which presents within 4 to 6 hours in an infant and typically greater than 24 hours for an adolescent or adult.[8][9][10]

Clinical Significance

While any deviation from normal, reduced or increased, is clinically relevant, the most clinically significant is an increased anion gap, particularly when associated with metabolic acidosis. In terms of DKA, this is the development of acetoacetate and B-hydroxybutyrate. In terms of Lactic Acidosis, it is the increased formation of and decreased metabolism of lactate.

Overall, the clinical significance has as its basis in detecting and aiding the body in handling, metabolizing or removing the inciting factor causing derangements in ion concentrations.

Pearls:

Every 1 g/L decrease in albumin will decrease the anion gap by 0.25 mmol/L. A patient with hypoalbuminemia may present with a normal anion gap when in actuality, they have a high anion gap acidosis. Consider in ICU patients. Another ratio worth adding to your anion gap toolkit is every decrease in 10 g/L albumin = 2.3 mmol/L decrease in the anion gap.

Interestingly, paraproteins such as IgG also cause a reduction in anion gap due to their positive charge. Thus, patients with monoclonal proliferation such as those suffering from IgG Myeloma have significant increases in cation or positive ion concentration resulting in decreased and rarely increased anion gaps. Likewise, a polyclonal proliferation of IgG would have the same effect, which can present in an HIV patient.

Finally, patients prescribed lithium carbonate for bipolar disorder can have reduced anion gap. At therapeutic doses of 1.0 mmol/L, no change in the anion gap materializes. However, in lithium intoxication, a noticeable reduction is appreciated.

Mnemonic to remember increased anion gap metabolic acidosis("CATMUDPILES"):

  1. Carbon monoxide/cyanide
  2. Aminoglycosides
  3. Theophylline
  4. Methanol
  5. Uremia
  6. Diabetic ketoacidosis
  7. Paracetamol/acetaminophen
  8. Iron/isoniazid
  9. Lactic acidosis
  10. Ethanol/ethylene glycol
  11. Salicylate/ASA

Mnemonic to remember normal anion gap metabolic acidosis ("USEDCARP")[11][12][13]:

  1. Ureterostomy
  2. Small bowel fistula
  3. Extra chloride
  4. Diarrhea
  5. Carbonic anhydrase inhibitor
  6. Adrenal insufficiency
  7. RTA
  8. Pancreatic fistula

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Biochemistry, Anion Gap - Questions

Take a quiz of the questions on this article.

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A 17-year-old male presents to the emergency department with tachypnea. After speaking with the parents, the patient has been experiencing polyuria and polydipsia for the past two weeks. Specifically, in the last three days, he has complained of increasing nausea and four episodes of vomiting. The patient is afebrile. The patient has no past medical history and vaccinations are up to date — no sick contacts. Diabetic ketoacidosis is suspected. In a patient not diagnosed with diabetes mellitus type I prior, what kind of acid-base values would be expected, and what corresponding anion gap would be plausible?



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Which of the following scenarios would one expect an increase in the anion gap that does not reflect an acid-base disturbance?



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A 56-year old female presents with 12-hour onset of ringing in her ears, abdominal pain, tachypnea, and nausea. She is difficult to calm and unable to gather history from. Prior medical charts reveal patient has a family history of coronary artery disease for which she takes aspirin 81 mg and major depression for which she takes fluoxetine 40 mg caps. The patients family reports she has been increasing flat lately, despite taking her medication as prescribed. They have been concerned about her potential to harm herself. Vitals signs are a respiratory rate of 32/minute, pulse of 102 bpm, blood pressure of 136/86 mmHg, and temperature of 100.9 F. Potassium is 3.0 mEq/L, bicarbonate is 18 mEq/L, pH is 7.1, and anion gap of 14. As the health care practitioner in charge of this patient, what be the suspected diagnosis and course of action?



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A 45-year-old man underwent an umbilical hernia repair with mesh placement. The perioperative course was uneventful except before surgery gastric contents had to be aspirated from the upper GI tract. The patient's past medical history includes gastroesophageal reflux disease and occasional panic attacks. Patients blood work shows sodium of 138 mEq/L, potassium of 3.5 mEq/L, and chloride of 75 mEq/L. ABG's drawn showed bicarbonate of 42 mmol/L, pH of 7.58, and PCO2 of 55. What are his primary acid-base disturbance and anion gap?



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A 66-year-old male is brought in by EMS for altered mental status. He has a past medical history of diabetes type II, hypertension, coronary artery disease, and Parkinson's Disease. His daughter reports that for the past three weeks he has seemed increasingly fatigued and inattentive. She said, “At first I didn’t think anything of it because he usually never remembers to drink water on his own, but for the past three weeks he has been drinking so much he has to go to the bathroom constantly. I thought he was getting better.” Patients at home medications include aspirin, metoprolol, atorvastatin, carbidopa-levodopa, and metformin. The daughter also reports that her father was admitted and successfully treated three weeks ago for pneumonia. Among the acute lab work, you notice a serum glucose of 924 mg/dL and serum osmolality of 328 mOsm/kg. You become concerned about an acid-base disturbance. ABG is ordered. Which of the following choices depicts the correct pH, anion gap, and explanation?



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A 38-year-old male physician presents to your clinic with a complaint of bloody sputum for the past two weeks. History is significant for three recent travel trips including one month in India and two months in Africa for medical mission trips. For the past two months, he has also lost 10 lbs and woken up in the middle of the night drenched in sweat. He believes the night sweats are due to nightmares of losing his current patients who are fighting infections of tuberculosis and malaria. After ordering and reviewing the appropriate labs, you diagnose the physician and start him on combination therapy for his condition. Two months later you learn he was admitted to the ICU at the local hospital due to a medication side effect. Prior to his admission, hospital records state he experienced fluctuating paresthesias in his lower extremities with burning pain. Requesting his labs, you notice the following: pH of 7.24, pCO2 of 32, PaO2 of 96, HCO3 of 18. His sodium is 144, potassium is 4.6, and chloride is 102. You realize the patient has a ___________ acid-base disturbance with an anion gap of ___ caused by _______ medication.



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Biochemistry, Anion Gap - References

References

Grifoni E,Piccini G,Parrinello M, Microscopic description of acid-base equilibrium. Proceedings of the National Academy of Sciences of the United States of America. 2019 Feb 14;     [PubMed]
Hopkins E,Sharma S, Physiology, Acid Base Balance 2019 Jan;     [PubMed]
Sharma S,Aggarwal S, Hyperchloremic Acidosis 2019 Jan;     [PubMed]
Schricker S,Schanz M,Alscher MD,Kimmel M, [Metabolic acidosis : Diagnosis and treatment]. Medizinische Klinik, Intensivmedizin und Notfallmedizin. 2019 Feb 6;     [PubMed]
Malkin HM, Historical review: concept of acid-base balance in medicine. Annals of clinical and laboratory science. 2003 Summer;     [PubMed]
Islam T,Sherani K,Surani S,Vakil A, Guidelines and controversies in the management of diabetic ketoacidosis - A mini-review. World journal of diabetes. 2018 Dec 15;     [PubMed]
Smolenski S,George NM, Management of ketosis-prone type 2 diabetes mellitus. Journal of the American Association of Nurse Practitioners. 2019 Feb 27;     [PubMed]
Bowers D,Mason M,Clinkscales M, Managing Acute Salicylate Toxicity in the Emergency Department. Advanced emergency nursing journal. 2019 Jan/Mar;     [PubMed]
Wittler M,Masneri DA,Hannum J, Chronic Salicylate Toxicity Simulation. MedEdPORTAL : the journal of teaching and learning resources. 2018 Aug 17;     [PubMed]
Brinkman JE,Sharma S, Physiology, Respiratory Alkalosis 2019 Jan;     [PubMed]
Srinivasan MP,Shawky NM,Kaphalia BS,Thangaraju M,Segar L, Alcohol-induced ketonemia is associated with lowering of blood glucose, downregulation of gluconeogenic genes, and depletion of hepatic glycogen in type 2 diabetic db/db mice. Biochemical pharmacology. 2019 Feb;     [PubMed]
Firestone RL,Parker PL,Pandya KA,Wilson MD,Duby JJ, Moderate-Intensity Insulin Therapy Is Associated With Reduced Length of Stay in Critically Ill Patients With Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State. Critical care medicine. 2019 Mar 7;     [PubMed]
Sharma S,Rawat D, Hypocarbia 2019 Jan;     [PubMed]

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