This is the first documentation of a spontaneous and nonspecific chemical reaction of an iodinated contrast media with ammonium persulfate used in As³⁺-Ce⁴⁺ catalytic spectrophotometry for urine iodine concentration (UIC) detection.

We herein report an incidental case who had a dual source computed tomography examination for papillary thyroid carcinoma diagnosis. Serial spot urine specimens were collected during her hospitalization and were measured by As³⁺-Ce⁴⁺ catalytic spectrophotometry on a Beckman Coulter AU5800. The reacted solutions were “brownish”, and the results showed extremely high iodine concentrations despite serial dilutions. The patient claimed no dietary habit of iodized salt or iodine-containing medical history, which strongly pointed to iodinated contrast media (ICM) via intravenous injection. Even with 0.01% ICM, its interruption is still profound on the desired urine iodine reaction with ammonium persulfate, leading to inaccurate UIC and possibly inappropriate treatment.

The following laboratory suggestions should be considered: (1) As³⁺-Ce⁴⁺ catalytic spectrophotometry is only suitable for UIC measurement after confirmed ICM renal clearance; (2) A mass spectrometry-based method can be applied as an alternative during the ICM clearance period; and (3) The UIC baseline can be confirmed after ICM injection by consecutive detection for at least 2 mo.

As the most widely used marker to assess the plasmatic iodine pool, urine iodine concentration (UIC) measurement is recommended to assess the iodine status of a population[1,2]. With the increased use of iodinated contrast media (ICM) for chest and neck computed tomography (CT), excess iodine exposure has increased in patients with thyroid disease (TD). Several studies suggest that ICM increases the total body iodine stores for at least 3 mo following contrast exposure and, in some situations, for as long as 2 years. The introduction of approximately 0.1% inorganic iodine free from ICM into serum might compete with radioactive iodine or disturb thyroid function due to the Wolff‒Chaikoff effect[3,4]. Considering that accurate UIC detection is very important to guide radioactive iodine treatment in patients with TD, it is necessary to understand the effect of excess iodine exposure on UIC after ICM injection in patients with TD.

The final diagnosis of the presented case was PTC.

The patient underwent radical thyroidectomy on January 15, 2020. Histological examination of the frozen sections from the resected lesion confirmed PTC.

The patient had a good recovery. Her thyroid function indicators were normal until this article is written.

For the determination of iodine in urine, As³⁺-Ce⁴⁺ catalytic spectrophotometry is recommended as the standard assay according to WS/T 107.2-2016 by the National Health and Family Planning Commission in China. The protocol is as follows: (1) Add 600 μL ammonium persulfate to 200 μL urine and digest the mixture for 60 min in a 100 °C incubator; (2) Transfer the digested mixture to a Beckman Coulter AU5800; (3) Add 120 μL reagent 1 containing As³⁺ to 25 μL digested mixture; (4) Add 36 μL reagent 2 containing Ce⁴⁺ to reduce the yellow Ce⁴⁺ to colorless Ce³⁺; and (5) The decreasing absorbance curve of Ce⁴⁺ at a wavelength of 410 nm is positively proportional to the concentration of iodine over a designated period of time[5]. On January 14, we incidentally found that the digested solution of a spot urine specimen as well as its 2-fold dilution was “brownish”. We contacted the patient, and she recalled that the specimen was collected within 1 h after intravenous ICM injection on January 13. The ICM was iohexol (35 g I/100 mL). We tested iohexol instead of urine in serial dilutions. The results strongly indicated that a chemical reaction immediately started once iohexol was mixed with ammonium persulfate, even prior to digestion (Figure 3A), and we perfectly reproduced the “brownish” solution as well as the solid purple precipitates (Figure 3B). We believe that this automatic chemical reaction would disrupt the desired reaction of urine iodine with ammonium persulfate and cause inaccurate sUIC values.

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Figure 3 Detection of the iodinated contrast media reagent iohexol by As³⁺-Ce⁴⁺ catalytic spectrophotometry. A and B: Solution appearances before (A) and after digestion at 100 °C for 60 min (from left to right: 175 mg, 35 mg, and 3.5 mg) (B); C and D: Ce⁴⁺ absorbance curve of 5-fold dilution of urine specimen on January 14 (C) or of 3.5 mg iohexol (D).

There are three important studies that provide convincing and detailed data on urine iodine clearance[6-8]. In general, if a patient undergoes intravenous contrast CT examination, it will take at least 1 mo for the UIC to return to the baseline level. Unfortunately, there is a lack of data for the Chinese population to date. As³⁺-Ce⁴⁺ catalytic spectrophotometry has a sensitivity of 10 μg/L and a reportable range of 0-3000 μg/L in our laboratory. Notably, the color shade of the spot urine specimen on January 14 was between those of 35 mg iohexol (100% renal clearance assuming 200 mL urine output) and 3.5 mg iohexol (90% renal clearance). More importantly, as shown in Figure 1B, the color faded for the 2-fold dilution and disappeared for the 5-fold dilution, which allowed us to speculate that the original urine specimen probably contained at least 17.5 mg iohexol (50% renal clearance). This value was very different from that calculated on January 14, which was 1.05 mg/L (Figure 1C). We also checked the Ce⁴⁺ absorbance curve for 3.5 mg iohexol. Consistent with the curve of the 5-fold dilution of urine specimens on January 14, there was a background optical density value indicating a nonspecific reaction (Figure 3C and D). Therefore, the spontaneous and nonspecific chemical reaction of ICM with ammonium persulfate used in As³⁺-Ce⁴⁺ catalytic spectrophotometry can interfere with the accuracy of the UIC results. It is very important to know the period for urine iodine levels to return to baseline after ICM injection and to collect urine specimens on the right time.

We suggest that the following scenarios should be considered for PTC patients who may have UIC measurement: (1) Pre-examination quality control of urine specimen. As³⁺-Ce⁴⁺ catalytic spectrophotometry is only suitable for the determination of the sUIC as well as the 24-h UIC after confirmed ICM renal clearance; (2) Appropriate laboratory methods for UIC detection. A mass spectrometry-based method can be applied as a favorable alternative during the ICM clearance period to evaluate potential ICM impairment; and (3) Optimal UIC detection intervals. The UIC should be detected for at least two consecutive months to confirm the baseline after ICM injection.