Physiological Intraluminal Uptake of ¹⁸F FDG in Gallbladder on PET/CT – A Retrospective Cohort study in North India

Introduction

¹⁸F 2-fluoro 2-deoxy-D-glucose positron emission tomography/computed tomography (¹⁸F FDGPET/CT) has been incorporated into the diagnostic algorithm for various oncological as well as nononcological diseases. Precise interpretation of the PET images necessitates distinguishing between the abnormal pathological FDG uptake from the physiological and normal variants.

The physiological distribution of FDG includes the brain, myocardium, liver, variable uptake in stomach and intestines, and finally excretion through the kidneys and urinary bladder.[1] The liver plays an important role in the regulation of glucose metabolism in the form of glycolysis and gluconeogenesis; thus, it has been used as the standard for the background activity and visual scoring of the grade of FDG uptake in various lesions.[2]

The pathological FDG uptake in gallbladder (GB) with anatomical changes is well-established in the malignancies[3] as well as in non-oncological conditions such as cholecystitis, adenomyomatosis, and pseudotumor.[456] Furthermore, there have been few reports and studies showing the incidental FDG uptake in GB lumen in the absence of any anatomical changes on adjunct CT or any clinical features.[78910] This physiological FDG uptake in GB can vary from the mild (less or similar to that of liver) to intense (more than liver) in nature and is imperative to distinguish such benign findings from the above-mentioned pathological conditions.

This study aims to evaluate the incidence and the factors that contribute to the physiological accumulation of FDG in GB lumen in the absence of any pertinent clinical history or anatomical abnormality on CT scan.

Materials and Methods

Results

Overall, 632 patients underwent ¹⁸F FDG PET/CT in the study period, of whom 82 (13.0%) showed physiological intraluminal FDG uptake in the GB [Figure 1]. These patients constituted the study group, while out of the remaining 550 patients, a random 149 patients formed the comparator group. In the study group, the median SUVmax of intraluminal uptake in GB was 2.1 (0.93) g/ml. Various parameters were compared between the two groups [Table 1]. Only the body mass index was similar between the groups. The study group had significantly lower SUVmax of liver (2.3 [0.8] vs. 2.8 [1] g/ml, P < 0.001) and blood pool (1.7 [0.7] vs. 2.2 [0.8] g/ml, P < 0.001) than the control group.

Close

Figure 1 Pictorial examples of the physiological accumulation of fluoro 2-deoxy-D-glucose uptake in gallbladder lumen, White arrows highlight the Physiological accumulation of FDG in the Gall Bladder without obvious CT changes

Export to PPT

We then studied the factors associated with intraluminal FDG uptake in the study group. Patients in the study group had significantly higher fasting blood sugar (101 [24] vs. 93 [18] mg/dl, P – 0.007), higher FDG dose injected (6.8 [2.5] vs. 6 [2.3] mCi, P < 0.001), and a longer time to scan (82 [54] vs. 78 [38] min, P – 0.02) as compared to control group. The lower SUVmax of both liver and blood pool in the study group, despite a higher FDG dose injected, signifies a higher FDG extraction from the blood pool in patients of the study group as the time to scan increases, which may then contribute to intraluminal FDG accumulation in GB.

Discussion

Besides the physiological areas of metabolism (brain, myocardium, and liver) and excretion (kidneys and urinary bladder), the other areas of physiological FDG uptake include brown adipose tissue,[12] bowel,[13] skeletal muscles,[14] growth plates in pediatric population,[15] lymphoid tissues in head and neck, thymus,[16] testes,[17] uterus and ovaries,[18] and lactating breasts.[19] The physiological FDG uptake in these areas is usually diffuse in nature and not associated with any morphological changes in the respective organs.

Few studies have documented GB as an uncommon site physiological FDG uptake and evaluated various factors associated with this. In a large cohort study, Asmar et al.[10] reported the incidence of the physiological FDG uptake in GB as 0.67% (54 out of 8096 cases) and associated with higher blood glucose than those without the GB uptake, without any significant difference in the injection–scan interval, SUVmax of liver and blood pool, as well as GB volume. In subgroup analysis, Murata et al.[9] also reported increased injection–scan interval showing FDG uptake in GB, and delayed scans showed more FDG uptake than the early scans. Calabro’ et al.[8] evaluated the factors showing FDG uptake in GB in 73 patients and found that though there was no significant association between the FDG uptake and injected FDG dose, image interpretation was more challenging in those injected with lower dose, thus may lead to false-negative results.

Our study reports a higher incidence of the FDG uptake in GB (13%), which is associated with higher blood glucose, longer injection-scan interval, and higher injected FDG dose. One likely reason for such higher incidence and association with higher injected dose could be that we assumed the physiological FDG uptake taking the blood pool (descending thoracic aorta) rather than taking liver as the reference standard. The accumulation of the FDG uptake in the GB lumen is likely due to its biliary excretion,[10] and the exact mechanism is still not fully understood. In normal bile, glucose is present in negligible amounts due to its active reabsorption by cholangiocytes after being secreted by hepatocytes. While both glucose and FDG initially enter canalicular bile via Glucose transporter type 2 (GLUT2), only glucose is subsequently reabsorbed into circulation through Sodium glucose cotransporter - 1 (SGLT-1) and Glucose transporter type 1 (GLUT-1) transporters.[20] Due to fluoride substitution on carbon 2, FDG is not recognized by SGLTs, resulting in its accumulation in the GB instead of reabsorption.[2122]

The quality control is done daily before the injection of FDG and also on any day, only few patients show this FDG uptake and rest of them show no uptake at all. Likewise in all the three studies, we also did not find any significant association between the physical patient characteristics such as height, weight and body mass index between the uptake and no-uptake groups, thus emphasizing that this GB uptake is largely related to the physiological biliary excretion or metabolism which needs to be further evaluated with dynamic PET studies. However, our finding of association of this GB uptake with higher blood glucose than the control group (no uptake) is interesting and different from large cohort study by Asmar et al.[10] and needs further dynamic studies to establish its role in the hepatic metabolism of FDG. Since the higher intraluminal FDG uptake can be observed in states of higher blood glucose, patients undergoing PET/CT for restaging and response assessment of the GB cancers should maintain stringent glycemic control at the time of scan to prevent erroneous interpretation.

The major strengths of this study include a decent sample size, semi-quantitative assessment of the physiological FDG uptake in GB, visual assessment from a single PET/CT scanner, and multifactorial analysis of the parameters related to the patient, procedure, and injected FDG dose. However, lack of follow-up of the patients exhibiting the physiological GB uptake owing to logistic reasons and lost to follow-up remain as one of the major limitations of this study. The significance of this high incidence of the physiological accumulation of FDG in GB lumen in the population of North India remains unclear, but still we postulate that this phenomenon is likely related to the metabolism and biliary excretion of FDG, which should be evaluated by the dynamic PET studies. We hypothesize that maintaining the fasting sugar levels of <100 mg/dl and time interval of 45–60 min between the FDG injection and scan is expected to decrease the incidence of physiological FDG uptake in the GB lumen. Furthermore, lesser the injected FDG activity, lesser the incidence of this physiological FDG uptake is expected. However, prospective studies are needed to confirm this hypothesis.

Conclusion

Physiological intraluminal FDG uptake in GB is present in about 13% patients undergoing ¹⁸F FDG PET/CT in the North Indian population. Patients with the higher fasting blood sugar, higher FDG dose injected, and a longer time to scan are more likely to have a physiological intraluminal FDG uptake in GB.