Tales of the Anion Gap, Part IV


The authors reviews several challenging cases illustrating the utility of the anion gap in the evaluation of an acidotic patient.

Tales of the Anion Gap, Part IV

Let us review a few challenging cases illustrating the utility of the anion gap in the evaluation of an acidotic patient. All of these are actual patients of whom I have taken care.

Recall that the evaluation of a patient with suspected metabolic acidosis should generally follow the following algorithm:

  • Is the patient acidotic?
  • Is the respiratory compensation appropriate?
  • Does the patient have an elevated or a normal anion gap acidosis?
  • If the anion gap is elevated, what is the unmeasured anion?

Recall, also:

  • That the normal anion gap in most clinical laboratories is about 6 with a standard deviation of 1.5
  • Each one gram/dl lowering of the serum albumin will lower the anion gap by about 2.5
  • Unmeasured anions can be classified as serum proteins, organic acids and inorganic acids, so that one or more of these must be responsible for an increased anion gap metabolic acidosis.

Case 1

A 71-year-old man presents with confusion and gait difficulty over the past several days. The patient had a history of multiple intestinal resections for small bowel adhesions and was left with a short gut, for which he, at one point, had been on TPN. However in recent months he had been able to tolerated a normal diet with mild diarrhea. He had recently completed a course of clindamycin for a dental abscess. He was noted to be a bit tachypneic but his vital signs were otherwise stable; he seemed confused and slurred his speech. Blood gases on room air showed: pO2 95, pCO2 29, pH 7.29, HCO3- 14. Chemistries showed: Na+ 143, K+ 3.7, Cl 103, CO2 14, BUN 21, Cr 1.2, Glu 152, Alb 3.7, phosphorus 3.1, L-lactate 1.02, and serum ketones 0.56. Acetaminophen and salicylate levels were zero, and serum osmolality was 299.

Applying our algorithm to this case, the patient certainly has a metabolic acidosis. His predicted pCO2 for a serum HCO3 of 14 would be estimated at (1.5 X 14=21)+8= 29, so his respiratory compensation is correct. The anion gap in this case is calculated at 26, so this is indeed an elevated anion gap acidosis. The delta ratio is approximately 20/12= 1.67.

What is the unmeasured anion in this case? The serum albumin is on the low edge of normal, so the unmeasured anion or anions must be organic or inorganic acids. The patient is not in renal failure and his serum phosphorus is normal, indicating that the unmeasured anion is probably not an inorganic acid. The clinically most important organic acids, lactic acid and B-OH are normal and therefore would not be playing a major role. Therefore, the unmeasured anion appears to be a truly unmeasured organic acid.

This situation is most suggestive of an intoxicant of some sort being metabolized to an organic acid. Intoxication with methanol (metabolized to formic acid) or ethylene glycol (to glycolic acid and oxalic acid) is ruled out by the patient’s normal serum osmolality. (This will later be discussed in more detail.)

The patient’s serum was sent to a reference laboratory which subsequently reported a D-lactate level of 8.3mmoles/L. The usual serum lactate assay measured in hospital laboratories measures metabolism by the L-lactate dehydrogenase enzyme and therefore measures only L-lactate, which was normal in this case. D-lactic acidosis is a syndrome of an elevated anion gap acidosis and neurologic compromise generally occurring in patients with short gut syndrome, usually post jejunoileal bypass, wherein ingested carbohydrate is metabolized by colonic lactobacilli to D-Lactate. In this case, the patient’s use of clindamycin may have promoted colonic bacterial overgrowth. The patient was treated with intravenous bicarbonate-containing fluids, a low carbohydrate diet and PO vancomycin and recovered uneventfully. It is noted that the elevated D-lactate probably does not account for the entire elevated anion gap, indicating the presence of smaller amounts of other organic acids. This case illustrates that organic molecules exist as stereoisomers, which may have different clinical effects, as well as testing.

Case 2

A 26-year-old woman is referred from a local ED because of recent weakness and difficulty walking. The patient had a diagnosis of scleroderma made about six years prior to admission and had a history of Raynaud’s phenomenon and GERD, as well as dermatologic stigmata on her face and hands typical of scleroderma, but had been feeling well until the last few days. Laboratory workup included: venous blood gases with pO2 42, pCO2 31, pH 7.17, and HCO3- 11. Blood chemistries showed: Na+ 141, K+ 1.7, Cl 117, CO2 12, PO4 2.3, Albumin 3.4, BUN 13, Cr 0.9, and lactic acid 2.0. Her urinalysis showed a dilute specimen with an alkalotic pH of 8.0.

Applying our algorithm, the patient certainly had a metabolic acidosis. Her calculated predicted pCO2 based on an HCO3- of 11 would be about 24.5, therefore her respiratory compensation is inadequate and indicates respiratory acidosis, as well. This may be related to the patient’s muscular weakness associated with the severe hypokalemia. The patient’s calculated anion gap is 12, which is elevated, however this is a case in which taking into account the patient’s hypokalemia and calculating the delta ratio is helpful. If the K+ level is taken into account, the normal anion gap would be about 10 and would be calculated at less than 14 here. Similarly, the delta ratio would be calculated at 0.43 on the original data and approximately 0.26 if the hypokalemia is accounted for. Therefore, it is evident that the primary metabolic issue in this case is a normal anion gap (hyperchloremic) metabolic acidosis.

This patient suffered from a Type I (distal) renal tubular acidosis (RTA) associated with her scleroderma. The primary defect relates to inability of the renal tubule to excrete protons, mostly in the form of ammonium ions. This may relate to a proton pump dysfunction in the distal tubule and leads to the kidneys excreting large amounts of potassium to maintain electrical neutrality. Type II (or proximal) RTA is caused by inability to reabsorb filtered bicarbonate in the proximal tubule and is therefore milder and less likely to produce hypokalemia. Both forms classically are considered primarily hyperchloremic acidoses, however an elevated anion gap is common, as in this case, in patients with Type I RTA and is seen less commonly in Type II RTA. Of course, some patients suffer from both forms of RTA. This patient improved very quickly with aggressive repletion of sodium bicarbonate and potassium acetate.

Case 3

A 77- year-old white woman presents with complaints of fatigue, back pain and polyuria. Her routine laboratory work demonstrated venous blood gases, showing a pCO2 37, pH 7.33, and HCO3 19. Among the rest of her lab work includes a normocytic anemia with a hemoglobin of 8.9g/dl and hematocrit of 29.9. Her blood chemistries showed a Na+ 127, K 5.1, Cl 101, HCO3- 19, BUN 26, Cr 3.2, Total Protein 12.4, Albumin 2.4, Calcium 12.8, Phosphorus 6.5, and Glucose 211.

Applying our algorithm to this situation, the patient would be considered to have a metabolic acidosis on the basis of her pH and serum HCO3- being out of the lower range of normal. The predicted pCO2 for a serum HCO3- of 19 would be approximately 36, so the respiratory compensation in this case is appropriate.

The patient’s calculated anion gap is 7, which is considered normal, but is this truly a normal anion gap metabolic acidosis?

The patient, of course, suffers from multiple myeloma.

Recall that Anion Gap = Unmeasured Anions minus Unmeasured Cations

Since, in both health and disease, the unmeasured cations are fairly constant at about 14 (counting K+), in calculating the anion gap, attention is primarily paid to the unmeasured anions. As previously mentioned, in normal states, the globulin fraction of protein does not exert a significant electrical charge and are usually ignored in our calculations (compared to the negatively charged albumin). Abnormal paraproteins may have a significant charge, though, particularly the positively charged IgG heavy chain and to a lesser extent the negatively charged IgA heavy chain. The amount of the charge will cause roughly a 0.8mEq reduction in the anion gap for every gram/dl of IgG heavy chain. In this patient, the IgG concentration was 6.3 gm/dl, which would reduce the anion gap by about 5. In addition, the elevated calcium level of 12.8 (versus a normal level of 10) would lessen the anion gap by another 1.4mEq, giving a total of about 6.4mEq.

In addition, the low serum albumin causes also causes a narrowing of the anion gap of approximately 2.5mEq for each gram/dl less than the normal range or approximately (2.5)(1.5)= 3.75.

Therefore, ‘correcting’ for both of these factors, we would adjust the originally calculated anion gap of 7 by roughly 6.4+3.7, leaving us with a ‘corrected’ anion gap of about 17. This relates to the patient’s renal failure, as well as small concentrations of lactic acid and B-OH. Therefore, this patient clearly has an elevated anion gap metabolic acidosis, despite the ‘normal’ anion gap.

Both malignant and benign monoclonal and polyclonal gammopathies may be associated with increased unmeasured cations and therefore a decreased anion gap. The presence of a very low or even negative anion gap in a healthy patient is often a laboratory error or otherwise of no concern, though can also be seen in lithium or bromide toxicity.

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