Abstract
Purpose
To compare normalisation to blood glucose (BG) with scaling to hepatic uptake for quantification of tumour 18 F-FDG uptake using the brain as a surrogate for tumours.
Methods
Standardised uptake value (SUV) was measured over the liver, cerebellum, basal ganglia, and frontal cortex in 304 patients undergoing 18 F-FDG PET/CT. The relationship between brain FDG clearance and SUV was theoretically defined.
Results
Brain SUV decreased exponentially with BG, with similar constants between cerebellum, basal ganglia, and frontal cortex (0.099–0.119 mmol/l−1) and similar to values for tumours estimated from the literature. Liver SUV, however, correlated positively with BG. Brain-to-liver SUV ratio therefore showed an inverse correlation with BG, well-fitted with a hyperbolic function (R = 0.83), as theoretically predicted. Brain SUV normalised to BG (nSUV) displayed a nonlinear correlation with BG (R = 0.55); however, as theoretically predicted, brain nSUV/liver SUV showed almost no correlation with BG. Correction of brain SUV using BG raised to an exponential power of 0.099 mmol/l−1 also eliminated the correlation between brain SUV and BG.
Conclusion
Brain SUV continues to correlate with BG after normalisation to BG. Likewise, liver SUV is unsuitable as a reference for tumour FDG uptake. Brain SUV divided by liver SUV, however, shows minimal dependence on BG.
Key Points
• FDG standard uptake value in tumours helps clinicians assess response to treatment.
• SUV is influenced by blood glucose; normalisation to blood glucose is recommended.
• An alternative approach is to scale tumour SUV to liver SUV.
• The brain used as a tumour surrogate shows that neither approach is valid.
• Applying both approaches, however, appropriately corrects for blood glucose.
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Introduction
In the use of 2-deoxy-2-fluoro-D-glucose 18 F-FDG positron emission tomography–computed tomography (PET/CT) for cancer management, some form of quantification of tumour uptake is essential in order to monitor treatment. This is most often done by measuring the standardised uptake value (SUV), which is the fraction of administered activity per millilitre of tissue, multiplied by an index of body size, usually weight. An alternative approach is to scale tumour count to the count rate from the liver, which in this context is assumed to be relatively constant. Because tumour SUV is inversely related to blood glucose, European Association of Nuclear Medicine (EANM) guidelines recommend normalisation of tumour SUV to blood glucose of 5 mmol/l [1]. This approach assumes a tumour glucose utilisation rate (MRGLU) that is independent of blood glucose, in which MRGLU would be equal to the product of tumour FDG clearance (ignoring the lumped constant [LC]) and blood glucose. Thus, insofar as tumour SUV is a surrogate for tumour FDG clearance, the guidelines assume a hyperbolic relationship between tumour SUV and blood glucose. EANM guidelines also recommend rescheduling the study if blood glucose is above 7 mmol/l, although most departments would tolerate levels up to 10 mmol/l.
Liver SUV (SUVliver) is thought to be relatively constant [2, 3] and so an alternative approach is to express tumour count rate as a ratio with liver count rate [4–7]. The validity of this approach has received recent attention given the potential effect of hepatic steatosis on liver FDG uptake. Several groups have examined the relationship between steatosis and SUVliver. The results, however, were conflicting [8–12], likely because the effects of blood glucose on hepatic SUV were ignored.
FDG is dynamically exchanged between hepatocytes and blood (Fig. 1), resulting in a hepatic FDG concentration that closely mirrors the blood concentration [13–16]. Indeed, it has been recommended that in small animal work, the liver is a better region than the heart for monitoring the time course of blood activity [15]. Because blood FDG concentration is dependent on blood glucose [13], the hepatic FDG signal, rather than being constant, is also dependent on blood glucose, as has been previously shown [17, 18], such that the tumour-to-liver ratio also depends on blood glucose.
The aim of this study was to compare the normalisation to blood glucose and scaling to the liver as correction procedures for quantification of tumour FDG uptake. Tumour SUV is highly variable in patients with cancer, so we used the brain as a surrogate for tumours to examine the effects of blood glucose. The justification for this relies on the premise that FDG uptake kinetics should be similar for tissues such as brain and tumour, but unlike liver, in which FDG is metabolically trapped.
In order to evaluate the impact of hepatic steatosis on scaling to the liver, we also compared the relationship between brain-to-liver SUV ratio and blood glucose in patients with and without hepatic steatosis. Finally, we explored an additional procedure that may be useful for correcting tumour FDG uptake for blood glucose.
Methods
Patients
This was a retrospective service evaluation based on 304 patients undergoing routine FDG PET/CT. We initially included a consecutive group of 156 patients over a two-year period (2011–2012). To increase the numbers of patients with low or high blood glucose levels, we included 148 additional patients with blood glucose levels > 6 (n =113) or < 4 (n = 35) mmol/l who underwent imaging between 2007 and 2012. Most patients were referred with cancer. Forty-seven patients were currently receiving chemotherapy and 56 had received chemotherapy previously.
All patients who visit our PET CT unit are asked to provide informed consent for use of any of their clinical data for publication, and all patients in this study did so.
PET/CT acquisition
Departmental protocol dictated that patients fast for at least 6 hours prior to their appointment. Blood glucose was measured using a glucometer (Accu-Chek Performa, Accu-Chek Inform II test strips; Roche Diagnostics, Indianapolis, IN, USA). FDG was injected intravenously via the antecubital fossa or hand. Patients were required to relax in a semi-recumbent position in a warm, quiet area during the uptake period. Imaging was performed 60 min post-injection of 400 MBq (±10 %) FDG.
A Siemens Biograph 64-slice PET with immediate non-enhanced CT imaging (120 kVp/50 mA—CARE Dose 4D; slice, 5 mm; pitch, 0.8; rotational speed, 0.5/sec), was used to cover the area from the orbital margin to the lesser trochanters. Arms were up, as arms down may result in artificial elevation of the liver FDG signal due to beam-hardening effects. Three-dimensional emission data were then acquired at 3 min per bed position (PET reconstruction: 4 iterations; subset, 8; Gaussian pre-filter; full width at half maximum (FWHM), 5 mm; matrix size, 168 × 168; zoom, 1).
Image analysis
Regions of interest (ROIs) were drawn over the right lobe of the liver (3 cm diameter, avoiding any focal lesions), frontal cortex (1.5 cm), basal ganglia (0.9 cm), and cerebellum (1.6 cm). The whole-body sweep did not include frontal cortex and basal ganglia in 107 patients. Maximum and average standardised uptake values (SUVmax and SUVave) were recorded for all four regions. An ROI identical to the liver ROI drawn on the PET image was drawn on the CT scan for measurement of CT density in Hounsfield units (HU). SUV in brain regions was multiplied by blood glucose and divided by 5 to give normalised SUV (nSUV).
Statistical analysis
The relationships between variables were quantified using Pearson’s linear regression analysis of continuous data. In addition, patients were categorised into six subgroups based on blood glucose within the following ranges (patient numbers in brackets): < 4 (59), 4–4.9 (76), 5–5.9 (38), 6–7.9 (38), 8–9.9 (58), and 10+ (35) mmol/l. Patients were also subdivided into those with hepatic steatosis (CT density < 40 HU; n = 71) and those without (>39 HU; n = 233) [19, 20].
Results
Relationship between blood glucose and hepatic CT density
There was an inverse relationship between blood glucose and hepatic CT density (R = −0.39, p < 0.0001; Fig. 2). Thus, patients with fatty liver tend to have high blood glucose.
Relationships of brain and hepatic SUV values with blood glucose
Cerebellar SUVmax declined non-linearly as a function of blood glucose (Fig. 3). The relationship was better fitted with an exponential function, the constant of which was −0.0993 mmol/l−1 (R = 0.75), than a hyperbolic function (R = 0.60). Corresponding exponential constants for frontal cortex and basal ganglia SUVmax were −0.119 mmol/l−1 (R = 0.76) and −0.114 mmol/l−1 (R = 0.75). Exponential constants for brain SUVave were similar: −0.113 (R = 0.77), −0.110 (R = 0.76), and −0.097 (R = 0.74) mmol/l−1 for the frontal cortex, basal ganglia, and cerebellum, respectively. In contrast, liver SUV increased non-linearly as blood glucose increased (Fig. 4).
Relationship between cerebellum-to-liver SUV ratio and blood glucose
The ratio of cerebellum-to-liver SUVmax declined non-linearly as blood glucose increased (Fig. 5). The relationship appeared hyperbolic (R = 0.83), as theoretically predicted (see Appendix; Eq. 12). The relationship between cerebellum SUVmax/liver SUVave and blood glucose was similar (data not shown).
Effect of hepatic steatosis on the relationship between cerebellum/liver SUV ratio and blood glucose
The relationships between cerebellum-to-liver SUV ratios and blood glucose were similar patients with and without hepatic steatosis, whether SUVmax or SUVave was the denominator (Fig. 6).
Correction of brain SUV for blood glucose
Correction of tumour SUV for blood glucose by normalisation to 5 mmol/l (nSUV) aims to abolish the dependence of tumour SUV on blood glucose, and the same should apply to the brain. However, normalisation gave nSUVmax values for the cerebellum that correlated in a complex manner with blood glucose (Fig. 7a, upper panel). Thus, there was a positive correlation up to blood glucose level of 7 mmol/l, with a gradient of ~1 SUV per mmol/l (R = 0.44; p < 0.0001), but no further increase above 7 mmol/l. The overall relationship was therefore better fitted with a second-order polynomial (R = 0.55).
Division of cerebellar nSUVmax by liver SUVmax almost abolished its relationship with blood glucose, leaving a small gradient of 0.04 SUV per mmol/l (R = 0.17; p < 0.01; Fig. 7b, upper panel). There was no difference in this relationship between patients with and without hepatic steatosis. Results were similar when cerebellar nSUVmax was divided by liver SUVave instead of SUVmax, although the correlation coefficient and regression gradient were slightly higher (Fig. 7b, lower panel).
Based on the exponential constant of −0.099 mmol/l−1 derived from the relationship between cerebellum SUVmax and blood glucose, multiplication of basal ganglia SUVave with e0.099.glucose gave corrected SUV values that showed no correlation with blood glucose (R = 0.03; Fig. 7a, lower panel). Application of this correction procedure to the frontal cortex yielded similar results (data not shown).
Discussion
Brain SUV as a function of blood glucose
FDG enters the cell using the same transport system and phosphorylation enzymes as glucose, but is then metabolically trapped. As Hasselbalch et al. [21] found no change in regional cerebral MRGLU in response to acute hyperglycaemia, elevated blood glucose levels should result in decreased FDG uptake in the brain. Accordingly, we found an inverse nonlinear relationship between brain SUV and blood glucose that was well fitted by an exponential function. An inverse relationship between brain SUV and blood glucose has been shown previously in works by others [22, 23]. Buchert et al. [24] showed that acute reversal of hyperglycaemia increased FDG uptake in the brain by up to 80 %, while Kawasaki et al. [25] found that mild hyperglycaemia affected the distribution of FDG uptake in the brain of normal subjects. Critically, exponential constants of the relationships between brain SUV and blood glucose in the current study were similar for the cerebellum, basal ganglia, and frontal cortex.
Validity of liver SUV for scaling tumour SUV: effects of steatosis and blood glucose
Liver SUV, in contrast to brain SUV, showed a positive relationship with blood glucose (Fig. 4). The brain/liver SUV ratio, therefore, showed a strong inverse relationship with blood glucose (Fig. 5). As theoretically predicted (Appendix), this was hyperbolic. Although much attention has recently been focussed on the influence of hepatic steatosis on the validity of liver SUV as a comparator for tumour FDG uptake [8–12], blood glucose clearly has a more dramatic effect than hepatic fat on the brain-to-liver SUV ratio. Recent studies addressing the validity of the fatty liver as a comparator did not consider the influence of blood glucose on hepatic SUV, even though patients with fatty liver disease tend to have high blood glucose, as shown in Fig. 2. Two recent studies from our group [26, 27] confirmed that when blood glucose is taken into account, FDG accumulation in the liver is increased in hepatic steatosis. However, as shown in the current study, steatosis has much less impact on scaling brain SUV to liver SUV in comparison to blood glucose.
Use of brain SUV as a surrogate for tumour FDG uptake
Hasselbalch et al. [21] measured MRGLU in the brains of normal subjects using the Sokoloff model. The authors showed that during acute hyperglycaemia in comparison to normoglycaemia, there was no change in global or regional MRGLU in cortical and subcortical grey matter. Most studies [23, 28–30], though not all [31, 32], have shown that tumour SUV also decreases at high blood glucose levels, as is recognised in both the EANM and the Society of Nuclear Medicine guidelines [1, 33]. Lindholm et al. [28] showed no change in tumour MRGLU in response to oral glucose loading in five patients with head and neck cancer. Moreover, Crippa et al. [29] recorded a decrease in mean SUV of 20 hepatic colorectal metastatic deposits from 9.4 to 4.3 in a study in which patients underwent imaging on two separate occasions: fasting, and following a glucose load that increased blood glucose from 5 to 9 mmol/l. Ishizu et al. [23] recorded a decrease in brain glioma SUV from 4.41 to 1.54 associated with an increase in blood glucose from 5.9 to 13.5 mmol/l. Insofar as the brain can be regarded as a surrogate for tumours, in that both display no change in MRGLU in relation to glucose levels, the liver clearly cannot be used as a tissue comparator for tumour FDG uptake.
Correction of tumour SUV for blood glucose
The similarity between brain and tumour FDG kinetics can be extended to the correction of tumour SUV for blood glucose. EANM guidelines recommend normalising tumour SUV to 5 mmol/l [1]. To be successful, this procedure is required to abolish any relationship between tumour SUV and blood glucose. Its validity in this respect is supported by some studies [34, 35] but not by others [31].
A critical assumption underlying the use of the brain as a surrogate for tumour FDG uptake is that MRGLU in the brain and tumours is independent of blood glucose. There is little robust quantitative data in the literature concerning the effects of blood glucose on tumour SUV. Assuming an inverse exponential relationship between tumour SUV and blood glucose, it can be calculated from the data of Lindholm et al. [28] that the exponential constant for tumours would be −0.1 to − 0.15 mmol/l−1. Based on the data of Crippa et al. [29], the constant would be about − 0.2 mmol/l−1, although their SUV values had very high standard deviations. Based on the data of Ishizu et al. [23], the constant would be −0.093 mmol/l. These estimated exponential constants are broadly similar to those recorded here for the brain (−0.099 to −0.119 mmol/l−1).
Given the variation in tumour SUV, it is difficult to determine the relationship between blood glucose and tumour SUV in large heterogeneous patient populations. Nevertheless, in such an attempt, Zhuang et al. [30] recorded a weak inverse correlation between tumour SUV and blood glucose, without indicating whether the relationship was hyperbolic, exponential, or linear. In contrast, in 248 patients with lung cancer, Hallet et al. [31] found no significant correlation between tumour SUV, expressed logarithmically (thereby implying an exponential relation), and blood glucose. Differing levels of metabolic activity across tumours would not rule out a unique exponential constant that could be universally applied to tumours, provided that tumour MRGLU, like brain MRGLU, is independent of blood glucose.
In the current study, normalisation failed to achieve independence of the brain nSUV in relation to blood glucose, and instead generated a significant nonlinear correlation (Fig. 7). However, when brain nSUVmax was divided by liver SUVmax, it showed almost no relationship with blood glucose, regardless of whether patients had hepatic steatosis (Fig. 7). This finding is consistent with Eq. 12 (Appendix), which shows that (tissue SUV [SUVi] × blood glucose)/SUVliver is constant. When brain nSUVmax was divided by liver SUVave instead of SUVmax, a moderate linear positive correlation remained with blood glucose. We believe this is the result of a ‘signal dilution’ effect on liver SUVave of excess hepatic fat, the distribution of which is not homogeneous [36]. Such a dilutive effect is less with SUVmax than SUVave because SUVmax is selectively based on a voxel that is relatively free of fat [26]. The correlation between brain nSUVmax/liver SUVave and glucose is then the result of higher levels of hepatic fat in patients with high blood glucose. As such, for this dual correction procedure, liver SUVmax is recommended. The sense of the procedure is evident when, for example, there is heavy uptake of FDG by bone marrow. This would reduce the availability of FDG uptake elsewhere and reduce left ventricular blood SUV (SUVLV) and SUVliver. Division of nSUV by SUVliver would then appropriately increase nSUV. Another attractive feature of this approach is that it avoids the emerging issue of the best whole-body index—weight, lean body mass, or body surface area—upon which to base SUV [37], since whatever index used for measuring SUV is cancelled out.
Multiplication of SUV by e0.099 x glucose (based on the exponential constant of 0.099 mmol/l−1 for the relationship between cerebellar SUVmax and blood glucose) is another potential correction procedure. It abolishes the relationship between basal ganglia SUV and blood glucose (Fig. 7a). If a constant of approximately −0.1 mmol/l−1 is not universal for tumours, this correction would then not be valid for tumours. Further work is needed to address this issue, particularly in regard to the independence of tumour MRGLU and blood glucose level.
Study limitations
Limitations of the study include its retrospective design and heterogeneous patient population. Whilst every effort was made to avoid any focal liver pathology when drawing the liver ROI, it is possible that covert pathology, such as diffuse colorectal micrometastases, may have increased liver SUV. Moreover, the frontal cortex and basal ganglia were included in the whole-body sweep in only two-thirds of the patients, although patient numbers were still high.
Conclusions
In conclusion, tumour FDG uptake cannot be factored to liver SUV because of the effects of blood glucose rather than any influence of hepatic fat. Normalisation of brain SUV to blood glucose results in a complex relationship with blood glucose and is therefore also invalid. Combining the two correction procedures, however, gives corrected values that show almost no relationship with blood glucose, and the success of this dual correction procedure is explained theoretically in the Appendix. Normalisation to blood glucose using an exponential constant could also be useful.
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Acknowledgments
The scientific guarantor of this publication is Michael Peters. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. The authors state that this work has not received any funding. No complex statistical methods were necessary for this paper. Institutional Review Board approval was obtained. Written informed consent was obtained from all subjects (patients) in this study. Some study subjects or cohorts have been previously reported in AJR 2014;203:643–8 and Eur J Radiol 2014;83:751–5. Methodology: retrospective, observational, performed at one institution.
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Appendix
Appendix
The EANM guidelines recommend normalisation of tumour SUV to blood glucose of 5 mmol/l. This presupposes a hyperbolic relationship (i.e., y = constant/x) between SUV and blood glucose.
MRGLU in tissues in which FDG is metabolically trapped is related to tissue FDG clearance rate (Zi) and blood glucose concentration (G), as follows [21]:
Where LC is lumped constant.
Rearranging Eq. 1 and ignoring LC,
Assuming MRGLU is constant, this indicates a hyperbolic relationship between Zi and G.
Tissue SUV (SUVi) is a surrogate for Zi but is not identical to it. It is related to Zi as follows.
where M(t) and area(t) are respectively the quantity of FDG accumulated in the tissue and the area under the blood FDG time-concentration curve at time t (60 min in the current study).
Substituting for Zi in Eq. 1
where V is tissue volume, W is body weight and M(0) is administered activity.
Rearranging Eq. 5
Substituting for M(t) in Eq. 4 and rearranging,
For typical FDG blood clearance half-times of around 50 min from completion of early mixing (~10 min) [20], area(60 min) is approximately proportional to C(60 min), where C(t) is the blood concentration of FDG. For example, comparing clearance half-times of 69 and 50 min, the concentration and area ratios are 1.28 and 1.11, respectively, similar to the corresponding ratios for half-times of 50 and 39 min (1.26 and 1.11); i.e., same error.
So, substituting C(t) for area(t) in Eq. 7 and ignoring the proportionality constant,
Analogous to Eq. 5,
Substituting for C(t) in Eq. 8,
Rearranging Eq. 10,
So SUVi/SUVLV, rather than SUVi, has a hyperbolic relationship with blood glucose and therefore more closely represents Zi. Because of the kinetics of FDG distribution between hepatocytes and blood, liver FDG concentration closely reflects blood FDG concentration [13–16]. In Eq. 11, therefore, SUVLV can be replaced by SUVliver:
Alternatively, the relationship between SUVi and blood glucose can be regarded as exponential, i.e.,
The exponential constant k is the fractional decrease in SUVi per unit increase in blood glucose, and intuitively should be constant for tissues that metabolically trap FDG. Tissue MRGLU would then be reflected by A.
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Keramida, G., Dizdarevic, S., Bush, J. et al. Quantification of tumour 18 F-FDG uptake: Normalise to blood glucose or scale to liver uptake?. Eur Radiol 25, 2701–2708 (2015). https://doi.org/10.1007/s00330-015-3659-6
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DOI: https://doi.org/10.1007/s00330-015-3659-6