Q&A column

Editors: Olga Pozdnyakova, MD, PhD, Geoffrey Wool, MD, PhD, David Bernard, MD, PhD & Raul S. Gonzalez, MD

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Q. Clinicians at my hospital doubt my prolactin results. They report patients with prominent pituitary adenomas who have normal prolactin results. There are other patients who have hyperprolactinemia but no adenoma or galactorrhea. In those patients, the prolactin concentrations remain elevated even after therapy. Can you clarify?

A. November 2025—A serum or plasma prolactin test is typically ordered when evaluating patients with galactorrhea, amenorrhea, infertility, hypogonadism, or a pituitary adenoma.

The only thing about prolactin that most doctors remember from medical school is that samples must be diluted to detect the hook effect, also known as the prozone effect. In this phenomenon, falsely low results may be detected when analyte concentrations are high relative to reagent antibody concentrations in sandwich immunoassays. Fortunately, most commercial prolactin immunoassays are not susceptible to the hook effect unless the prolactin concentrations are extremely high, but even then they will still give an elevated result.¹

One quarter to half of pituitary adenomas do not increase serum prolactin concentrations—because they are nonfunctioning adenomas or “silent” prolactinomas (with no hormonal secretions), or because they secrete hormones other than prolactin.^2,3

A more common challenge for prolactin immunoassays is macroprolactin interference. Macroprolactin is a stable complex of prolactin and antiprolactin autoantibodies that is biologically inactive but persists in the bloodstream. It can be found in up to nine percent of people and is usually detected by retesting the sample after precipitating proteins with polyethylene glycol.⁴

1. Raverot V, Perrin P, Chanson P, Jouanneau E, Brue T, Raverot G. Prolactin immunoassay: does the high-dose hook effect still exist? Pituitary. 2022;25(4):653–657.
2. Drange MR, Fram NR, Herman-Bonert V, Melmed S. Pituitary tumor registry: a novel clinical resource. J Clin Endocrinol Metab. 2000;85(1):168–174.
3. Pei Z, Fang Y, Mu S, et al. Perioperative fluctuation and overall evaluation of adenohypophyseal hormone secretion in patients with nonfunctioning pituitary adenoma. Neurosurg Focus. 2022;53(6):E10.
4. Šostarić M, Bokulić A, Marijančević D, Zec I. Optimizing laboratory defined macroprolactin algorithm. Biochem Med (Zagreb). 2019;29(2):020706.

Chinedum Okafor, MD
Resident
Louisiana State University Health Shreveport
Shreveport, La.
Junior Member, CAP Accuracy-Based Programs Committee

Darryl Palmer-Toy, MD, PhD
Physician Director
Regional Reference Core Laboratories
Kaiser Permanente Southern California
Los Angeles, Calif.
Member, CAP Accuracy-Based Programs Committee

We periodically publish questions and answers that appeared in this column in past years and that remain relevant. The following question was published in the August 2021 issue and answered by James D. Faix, MD, a member then and now of the CAP Clinical Chemistry Committee. The answer was updated for publication in this issue by Clinical Chemistry Committee member Brian Naidrin Chang, MD.

Q. Is it necessary for a lab to report a corrected sodium level when the glucose level is really high? Studies show pseudohyponatremia can occur due to hyperglycemia. How common is this, and how do we decide which correction factor to use? Is it possible that this is easily overlooked by providers due to comorbidities in patients? Some references say there is a need to correct glucose for each 100 mg/dL increase above 400 mg/dL.

A. Sodium (and its accompanying anions chloride and bicarbonate), glucose, and urea are the major contributors to plasma osmolality. But only sodium and glucose contribute to effective osmolality (also called tonicity). Because sodium and glucose cannot cross cell membranes without active transport, both solutes influence the movement of water between the intracellular and extracellular compartments in ways that urea, which can passively move across cell membranes, does not.

Pseudohyponatremia is essentially a laboratory artifact that occurs when measuring sodium by specific methodologies.¹ Most modern high-throughput automated analyzers use indirect potentiometry to measure sodium, potassium, and chloride, which involves diluting the sample first. Normal plasma is composed of approximately 93 percent water and seven percent lipids and proteins. When lipids or proteins are significantly elevated (for example, in a patient with monoclonal gammopathy), the instrument does not correct for the reduction in plasma water content, leading to a falsely low sodium result. This limitation does not occur when measuring sodium via direct potentiometry methods commonly used by blood gas instruments because there is no dilution step.

Unlike pseudohyponatremia, hyponatremia associated with hyperglycemia reflects a true reduction in plasma sodium concentration. Increased plasma glucose causes a shift of intracellular water into the extracellular space, thereby diluting sodium. Similarly, increased glucose filtration by the kidneys results in glycosuria, which subsequently leads to increased losses of sodium and water via osmotic diuresis. During the process of treating hyperglycemia, it is critical for physicians to replace the sodium and water that has been lost. Closely monitoring plasma osmolality and electrolyte levels ensures that the optimal type and volume of resuscitation fluid is given. Although plasma osmolality can be directly measured in the laboratory with the proper instrumentation, it is more often derived from sodium, glucose, and urea nitrogen values. Again, it is important to keep in mind that although urea contributes to osmolality, it does not affect tonicity. Consequently, there is often interest in correcting the sodium level for the degree of hyperglycemia to better guide the replacement of sodium and water as glucose levels fall because of severe complications related to rapid overcorrection, such as central pontine myelinolysis.

Several calculations for determining a correction factor have been proposed in the literature. More than 50 years ago, Katz proposed a correction factor of a 1.6 mmol/L increase in sodium for every 100 mg/dL increase in glucose above 100 mg/dL.² Years later, Hillier determined that a mean factor of 2.4 mmol/L per 100 mg/dL was appropriate by inducing acute hyperglycemia in healthy people.³ More recently, Wolf developed a physiochemical model of hyperglycemia-induced sodium changes and proposed that the correction factor was significantly less than 1.6 mmol/L and in some cases approached 1 mmol/L.⁴ It is important to note that any calculation needs to take into consideration many factors, including the level of glycemia (the slope of hyponatremia changes as the level of glucose rises above 400 mg/dL) and the patient’s body composition, which may alter the distribution of total body water. Furthermore, critically ill patients, such as those in diabetic ketoacidosis or hyperosmolar coma, can have much more complex fluid and electrolyte balance compared to healthier people.

Hyponatremia due to hyperglycemia is relatively well recognized by endocrinologists and critical care physicians. However, there does not appear to be consensus regarding which correction factor is best, perhaps because no one calculation can apply to all patients due to a myriad of factors, including those discussed here. Therefore, it is probably best to allow health care providers to rely on their own experiences and decide for themselves which correction calculation to use rather than have the laboratory make that choice by reporting a corrected sodium level.

1. Weisberg LS. Pseudohyponatremia: a reappraisal. Am J Med. 1989;86(3):315–318.
2. Katz MA. Hyperglycemia-induced hyponatremia—calculation of expected sodium depression. N Engl J Med. 1973;289(16):843–844.
3. Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999;106(4):399–403.
4. Wolf MB. Hyperglycemia-induced hyponatremia: reevaluation of the Na+ correction factor. J Crit Care. 2017;42:54–58.