Although the abilities to trap iodine and produce thyroglobulin are unique features of thyroid tissues, physiological uptake of radioiodine can also be observed in a variety of non-thyroidal tissues ( and ). Two main causes of uptake include functional NIS expression and metabolism related to or the retention of excreted iodine. Expression of NIS in salivary and lacrimal glands, stomach, choroid plexus, ciliary body of the eye, skin, placenta, lactating mammary gland, thymus, and, to a lesser extent, the prostate, ovary, adrenal gland, lung, and heart has been demonstrated [4
]. Liver is regarded as the major organ for metabolism of radioiodinated thyroglobulin released from functioning thyroid tissues [26
]. Retention of radioiodine can occur as a result of structural or functional changes in any part of the body located along the route of radioiodine excretion or blood pooling ().
Figure 3 Schematic presentation of the locations of physiologic uptake and possible sources of contamination of radioiodine whole-body scan (WBS) .
Figure 4 Physiologic uptakes of radioiodine in the whole body; A - planar scintigraphy, B - SPECT/CT. Radioiodine uptakes in nasal secretion (1), parotid gland (2), dental prosthesis (3), remnant thyroglossal duct (4), remnant thyroid tissue (5), liver (6), and (more ...)
Physiologic radioiodine uptake
Breast is the one of major organs expressing NIS. Iodine accumulation in the lactating breast has been recognized for 60 years and is now regarded as a usual finding in postpartum patients [27
]. Once the NIS gene was cloned and become available for study, expression of NIS on the basolateral membrane of alveolar cells in mammary glands and marked induction during lactation were demonstrated [28
]. Bakheet et al. [30
] conducted an analysis of patterns of radioiodine uptake in lactating breasts on 20 radioiodine scintigraphic images. They identified four patterns of uptake: "full" (most common), "focal", "crescent", and "irregular". Uptake was asymmetric in 60% (left > right in 45%, right > left in 15%), symmetric in 25%, and unilateral in 15% of cases. Recognition of those patterns and clinical history is helpful to interpretation of breast uptake on radioiodine scintigraphy (). However, breast uptake that presents with an atypical pattern and/or is clinically unexpected may be interpreted as lung metastases.
Figure 5 Physiologic radioiodine uptake in the breast; A and B - planar scintigraphy, C - SPECT/CT. Unusual uptakes in lower thorax are observed in a nonlactating, 48 year-old female (A, arrows). Following mammography and breast ultrasonography showed negative (more ...)
The significance of radioiodine uptake by the non-lactating breast has also been studied by Hammami et al. [31
]. Approximately 6% of all female patients presented with breast uptake unrelated to lactation and the patterns were similar to those observed during breast feeding. Expressible galactorrhea and moderately elevated prolactin levels were observed in 48% and 24% of cases, respectively. According to findings from a recent case report, a 52-year-old female patient presenting with bilateral increased breast uptake was found to have hyperprolactinemia caused by prolactinoma in the pituitary gland [32
]. Enhanced NIS expression caused by hyperprolactinemia or individual variations might be a possible mechanism of radioiodine uptake in non-lactating breast.
Hammami et al. [31
] suggested the cautious interpretation of radioiodine uptake in the breast when: (a) A history of breastfeeding is not obtained or occurrence of breast uptake without breastfeeding is not acknowledged, (b) The uptake is irregular or unilateral, (c) There is a coexisting lung (or other) metastasis, (d) There is a coexisting elevated thyroglobulin level but an otherwise unremarkable scan.
Thymic radioiodine uptake is not an unusual finding on radioiodine WBS (). In a review of 175 patients, thymic uptake was observed in 1.2% (4/325) of diagnostic scans and 1.5% (3/200) of post-treatment scans in six patients [33
]. Patients were females between the ages of 22 and 51 years at the time of diagnosis. Wilson et al. observed that physiological thymic uptake was seldom apparent (with one exception; the youngest) on the scan performed at 3-4 days but was clearly observed on the 7-day scan [34
]. The pattern of uptake showed either a diffuse or a dumbbell shape. Overall consensus is that thymic uptake tends to become more evident on delayed imaging, with a therapeutic dose, in younger patients, and with less residual or metastatic thyroid tissues [33
Figure 6 Physiologic uptake of radioiodine in the thymus and stomach; A - planar scintigraphy, B - SPECT/CT. An arrowhead-shaped radioiodine uptake in upper mediastinum is noted in a 16 year-old female (A, 1). SPECT/CT revealed it as physiologic uptake in the (more ...)
The mechanism of radioiodine uptake by the thymus is not yet fully understood. Autoradiography performed by Verminglio et al. [35
] revealed localization of iodine uptake in the thymus to Hassall’s bodies, which are constituted by epithelial cells resembling keratinocytes. They suggested that this finding reflects the structural similarity between cystic Hassall’s bodies and thyroid follicles. Although a capability of transport and concentration of iodine is weaker in the thymus, compared with that presented in the thyroid gland, the presence of NIS is a proven mechanism of radioiodine uptake in the thymus [40
Following findings reported by Michigishi et al. [36
] will be helpful in differentiating physiologic from malignant mediastinal uptake: (a) uptake that becomes more prominent with repeated treatment, (b) requirement of higher than usual iodine doses in order to visualize the area, (c) a young age, (d) a large thymus on CT, and (e) a low serum thyroglobulin level.
Diffuse hepatic uptake of radioiodine is also a common finding on radioiodine WBS. Several authors have suggested that diffuse uptake of radioiodine by the liver is related to residual thyroid tissue or recurrent or persistent metastasis [26
]. According to Chung et al. [26
], whose study included a large population, because the liver is the major organ for the metabolism of thyroid hormones, this finding was explained by accumulation of radioiodinated thyroid hormones in patients with remnant thyroid tissues. In patients without thyroid remnant, radioiodinated thyroglobulin released from functioning cancer tissue is regarded as the cause of diffuse hepatic uptake of radioiodine.
However, other investigators have stated that diffuse hepatic uptake is a benign finding without clinical importance [42
]. Tatar et al. [44
] reported no significant association between liver uptake and uptake in the thyroid bed, the dose of radioiodine administered for ablation therapy, thyroglobulin levels, age, stage of disease, presence of local or distant metastases, recurrence, or survival. A more recent study of a larger population conducted by Omur et al [42
] also revealed no correlation of hepatic uptake with serum thyroglobulin levels, thyroid remnant score, and presence of local or distant metastatic foci. Instead, of particular interest, hepatic uptake showed positive correlation with administered doses of RAI, increased hepatic enzymes, and hepatosteatosis. This finding supports the concept that the presence of multiple metabolic factors is related to diffuse hepatic radioiodine uptake. They suggested that associated changes in lipoproteins and hepatic enzymes might have contributed to increased hepatic uptake in patients with hepatosteatosis. The increase of hepatic enzymes is an indication that delayed action of deiodinase may result in delayed excretion of iodine taken up by hepatocytes and consequent higher liver retention. NIS can also contribute to hepatic radioiodine uptake through mediation of active transport in association with iodine in intrahepatic bile ducts.
Studies of physiologic radioiodine uptake in the liver are summarized in . Obviously, hepatic visualization tends to occur more frequently in post-therapy scanning, compared with diagnostic scanning, and delayed scanning (8-10 days), compared with early scanning (4-5 days). According to our observations, in studies where an early scan was performed, hepatic visualization appears to be associated with functioning thyroid tissues, whereas it was not in studies performed using a delayed scan (). This discrepancy may be owing to differences in biological characteristics for trapping or excretion of radioiodine in remnant thyroid tissue, metastatic thyroid tissue, and liver with passage of time.
Review of diffuse hepatic uptake of radioiodine
The gestational sac can also be a site of radioiodine accumulation [45
]. Although the molecular mechanisms of iodine transport from mother to fetus are not clear, iodide and small amounts of thyroid hormones are transferred through the placenta from mother to fetus. Functional NIS expression in normal human placenta, preferentially in cytotrophoblastic cells, can also be a cause of radioiodine uptake in the gestational sac [46
Physiologic dilatation of the vessel, gut, duct, and ureter, regardless of the presence of obstruction, causes retention of body fluid containing radioiodine. Vascular dilatation of common carotids [48
], thoracic aorta [49
], and greater saphenous vein [50
] have been reported. Displaced blood pool activity associated with pectus excavatum can also be misinterpreted as abnormal radioiodine uptake in the chest [51
]. Menstruation history, even in young patients who have not yet reached menarche, should be considered in evaluation of unusual pelvic uptake of radioiodine [52
]. Retention of tears, saliva, gastric juice, bronchial secretion, bile, intestinal secretion, and urine can be related to a specific disease or clinical situation, such as epiphora, use of aerosol, achalasia, diverticulum, hiatal hernia, gastric volvulus, and ectopic kidney () [48
]. Meckel’s diverticulum has an additional mechanism of radioiodine uptake via NIS, which is originally expressed in gastric mucosa.
Figure 7 Physiologic uptake of radioiodine in the gallbladder and intestines; A - planar scintigraphy, B - SPECT/CT. Focal and segmental uptakes in right upper and left abdomen are noted (A, 1-2). SPECT/CT revealed them as physiologic uptakes unrelated to metastatic (more ...)
Various cystic structures, including the nasolacrimal sac, pleuropericardial, bronchogenic, thymic, breast, hepatic, renal, ovarian, epithelial and sebaceous cysts are also known to show false-positive findings on radioiodine WBS () [71
]. Entry of radioiodine into cysts occurs via passive diffusion or partially active transport; then, due to the slow exchange of water and chemical elements between the cysts and their surrounding extracellular/extravascular environment, it becomes trapped within the cysts. Although the mechanism is unclear, diffuse radioiodine uptake in bone marrow (bilateral femur and tibia) of patients involved in heavy running activity has also been reported [80
Figure 8 Physiologic uptake of radioiodine in a simple cyst of the right kidney; A - planar scintigraphy, B - SPECT/CT, C - abdominal CT. Focal tracer uptake is noted at the right side of the abdomen (A, arrows). SPECT/CT (B) and abdominal CT (C) images revealed (more ...)