High-titre circulating tissue transglutaminase-2 antibodies predict small bowel villous atrophy, but decision cut-off limits must be locally validated.

Numerous studies suggest that high levels of circulating immunoglobulin (Ig)A tissue transglutaminase (TTG2) antibodies predict coeliac disease with high specificity. Accordingly, it has been suggested that duodenal biopsy may not be required routinely for diagnostic confirmation where quantitative serology identifies the presence of high antibody titres. However, defining a cut-off TTG2 threshold is problematic, as the multiple available assay methods are not harmonized and most studies have been focused on the paediatric population. Recent paediatric guidelines proposed a TTG2 antibody diagnostic cut-off at 10 × the upper limit of normal (ULN) for the method; however, concerns remain about errors of generalization, between both methods and laboratories. In this study, we used retrospective laboratory data to investigate the relationship between TTG2 antibody levels and Marsh 3 histology in the seropositive population of adults and children at a single centre. Among 202 seropositive patients with corresponding biopsies, it was possible to define a TTG2 antibody cut-off with 100% specificity for Marsh 3 histology, at just over 10 × ULN for the method. However, UK National External Quality Assurance Scheme returns during the study period showed a wide dispersion of results and poor consensus, both between methods and between laboratories using the same method. Our results support the view that high-titre TTG2 antibody levels have strong predictive value for villous atrophy in adults and children, but suggest that decision cut-offs to guide biopsy requirement will require local validation. TTG2 antibody assay harmonization is a priority, in order to meet the evolving requirements of laboratory users in this field.

Non-invasive measurement of renal blood flow with 99mTc DTPA: comparison with radiolabelled microspheres.

This technique for non-invasive measurement of renal blood flow is based on the principle of fractionation of cardiac output, and applicable with any recirculating gamma activity tracer. It effectively determines the count rate that would be recorded over the kidney if the tracer behaved like radiolabelled microspheres and was completely trapped in the kidney on first pass. After correction for kidney depth, the estimated first pass activity plateau, expressed as a fraction of the injected dose, is equal to the kidney's fraction of cardiac output. The principle of the technique was validated by comparison with renal blood flow based on radiolabelled microspheres. Nine separate comparisons were made in two anaesthetised dogs. A known dose of 99mTc radiolabelled microspheres (particle size 23-45 microns) was injected into the left ventricle and the count rate over each kidney recorded. A known dose of 99mTc diethylenetriaminepenta acetic acid (DTPA) was then given as an intravenous bolus and the data recorded dynamically with a gamma camera online to a computer. After subtraction of the stable signal arising from the preceding radiolabelled microspheres, the theoretical first pass activity plateau from the DTPA that would have been recorded if the DTPA, after reaching the systemic circulation, had behaved like radiolabelled microspheres and become completely trapped in the renal vascular bed, was estimated. Using doses based on syringe counts before and after injection the ratio of renal blood flow values given by the two techniques (DTPA:RLMS) was 1.14 (SD 0.22) for the left kidney and 1.1(0.17) for the right. Using doses based on whole body counts, corresponding ratios were 1.05(0.11) and 1.02(0.13).(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of splenic blood flow in the anaesthetised dog using electromagnetic flowmetry and indium labelled platelets.

Splenic blood flow has been measured in the dog using indium labelled autologous platelets (SBFp) and compared with splenic blood flow measured with an electromagnetic flowmeter placed on the splenic vein (SVBF). The overall correlation between SBFp and SVBF was only moderately close (r = 0.54, P less than 0.01) and SBFp was about half SVBF. When expressed as a change between sequential measurements in an individual animal, the correlation between SBFp and SVBF was closer (r = 0.85, P less than 0.001). It was concluded that SBFp is a specific measure of splenic pulp blood flow and that the discrepancy between SBFp and SVBF reflects the degree of splenic blood flow bypassing the pulp.

Platelet kinetics in congenital heart disease.

The survival of 111indium labelled platelets has been determined in a series of 47 subjects comprising nine with cyanotic congenital disease (Eisenmenger's syndrome), seven with congenital heart disease associated with left to right shunts, six with primary pulmonary hypertension, six with peripheral vascular disease, 11 with cardiac disorder associated with low cardiac output and eight normal volunteers. Compared with the value in the normals of 9.5 days, mean survival was significantly shortened in those with Eisenmenger's syndrome (8.4 days) and with peripheral vascular disease (8.5 days). It was normal in patients with left to right shunts (9.5 days). Gamma camera imaging in selected patients failed to reveal any abnormal sites of deposition of labelled platelets except in one patient with peripheral vascular disease who had bilateral abnormal activity in his lower limbs and a shortened platelet survival (8.0 days). From theoretical considerations, it was concluded that the reduction in platelet survival in Eisenmenger's syndrome was such that, had it been the result of pulmonary intravascular platelet deposition, abnormal activity should have been visible on chest scanning with the gamma camera. The absence of scintigraphic evidence of abnormal platelet deposition in the lungs of these patients, combined with the linear configuration of their platelet survival curves, suggests that the accelerated platelet destruction is in the reticuloendothelial (RE) system rather than intravascular. Indirect evidence in favour of increased RE destruction of platelets in Eisenmenger's syndrome was the finding of an approximate doubling of intrasplenic platelet transit time, indicating abnormal platelet pooling within the spleen.

Continuous imaging of regional myocardial blood flow in dogs using krypton-81m.

The unique physical properties of the freely diffusible gas krypton-81 m allowed continuous imaging of regional myocardial blood flow in dogs when infused into the aortic root. Regional changes in myocardial perfusion related to transient coronary artery occlusion were demonstrated both as high resolution gamma camera images and as a quantitative strip chart record.

Clinical ventilation imaging with In-113m aerosol: a comparison with Kr-81m.

Following routine ventilation (Kr-81m)/perfusion (Tc-99m) scanning, we obtained aerosol ventilation scans using a solution of In-113m albumin and a settling-bag system. The large-volume settling bag reduces deposition of particles in the large airway by removing large droplets. The patient inhales the aerosol with 5-10 min of tidal breathing, then lung scans are obtained on a gamma camera. The energy of In-113m allows the ventilation scanning to be performed after Tc-99m perfusion scanning. Semiquantitative scoring of regional ventilation showed a close correlation (r = 0.97) between Kr-81m and In-113m aerosol ventilation scans. The aerosol technique gave a slight underestimation of ventilation compared with Kr-81m. This is explained by a slightly reduced penetration of particles to the periphery of the lung in patients with severe obstructive airways disease. In all cases, however, the aerosol did visualize all ventilated regions. The results indicate that this readily available aerosol technique can be useful for clinical ventilation imaging in multiple views.

A retrospective study of radiolabeled granulocyte kinetics in patients with systemic vasculitis.

Patients with systemic vasculitis, including Wegener's granulomatosis (WG) and microscopic polyarteritis (MP), may undergo white cell scanning for the investigation of infective complications and/or occult fever. In a retrospective study of 12 patients with systemic vasculitis (six each of WG and MP), all with renal disease, we observed increase diffuse lung radioactivity soon after the injection of 111In-labeled granulocytes or 99mTc-HMPAO-labeled leukocytes in all patients with WG and in three with MP. Lung activity was quantified by comparison with the liver or spleen. The lung:liver count rate ratio per pixel, 1-1.5 hr after injection, in patients with systemic vasculitis was 0.87 (s.d. 0.25), significantly higher (p less than 0.001) than the ratio 0.38 (0.13) in patient controls who had normal white cell scans. The majority of patients with systemic vasculitis had scintigraphic evidence of abnormal splenic function. Two had focal splenic defects, while 7 had increased labeled cell uptake. Nine of the patients with vasculitis showed cell migration into the gut, presumably as a result of vasculitis, and in 6 it was prominent. Focal nasal uptake was found in 5/7 patients with systemic vasculitis who had their heads imaged, and may be specific for WG. Although all patients had renal disease, there was scintigraphic evidence of diffuse parenchymal renal uptake of 111In-labeled granulocytes in only one (with MP). The presence of anti-neutrophil cytoplasmic antibodies did not correlate with any abnormality or with lung uptake. Systemic vasculitis is associated with abnormalities of granulocyte kinetics, particularly involving the lung and spleen.

A comparison of 111In with 52Fe and 99mTc-sulfur colloid for bone marrow scanning.

Under most circumstances 52Fe, 111In, and colloid show a similar distribution of marrow. The lesser uptake of 111In by liver and spleen may occasionally be of value in permitting visualization of that portion of the spinal marrow obscured by these organs in the colloid scan. However, in red cell aplasia, when there is dissociation between phagocytic and erythropoietic functions, scanning with 111In gives no information about erythropoietic tissue distribution. Therefore, indium cannot be used as an analog for iron in the study of the hematopoietic system.

Methods of measuring splenic blood flow and platelet transit time with In-111-labeled platelets.

Following bolus intravenous injection of In-111-labeled autologous platelets in humans, splenic blood flow (SBF) was measured by compartmental analysis of the equilibration of platelets between blood and the intrasplenic platelet pool. The result correlated closely (r = 0.94, p less than 0.001) with SBF measured from analysis of the first-pass time-activity curve recorded over the spleen by external detection. The intrasplenic platelet transit time (tp), measured concurrently with SBF from compartmental analysis, correlated closely (r = 0.78, p less than 0.001) with tp measured from deconvolution analysis. These correlations appear to support the use of compartmental analysis of the equilibration of radiolabeled platelets between blood and the intrasplenic platelet pool as a valid technique for the simultaneous measurement of SBF and tp. Both of these parameters have potential clinical usefulness for the understanding of intrasplenic platelet kinetics in a variety of disorders.

Indium-111-labeled autologous leukocytes in man.

Autologous leukocytes have been isolated, labeled with indium-111, and administered to 15 patients suspected of inflammatory disease. The stability of the label has been demonstrated and the in vivo kinetics and distribution of the labeled cells studied. The distribution is influenced by the type and viability of the cells separated by three different techniques. Generally, there was initial accumulation of radioactivity in the lungs; approximately half of this cleared in 15 min and the remainder slowly. Twenty-five to 50 percent of the radioactivity subsequently distributed in the spleen, liver, and bone marrow, and these did not show significant change with time up to 48 hr post injection. The In-111 radioactivity administered as labeled leukocytes free from erythrocytes cleared from the circulating blood with a half-time of 7.5 hr. In three of 15 patients, the suspicion of inflammatory disease could not be confirmed, and in these a normal distribution of radioactivity was observed. In the remaining 12 patients, focal accumulation of radioactivity was detectable within 4 to 24 hr after administration, and subsequent confirmation of sepsis was obtained. From three such patients, samples of abscesses were recovered which showed markedly higher radioactivity than that in the same weight of blood.

Indium-111 whole-body retention: a method for quantification of disease activity in inflammatory bowel disease.

Quantification of disease activity in inflammatory bowel disease (IBD) has been by measurement of fecal excretion of 111In-granulocytes. The difficulties of this method prompted us to evaluate quantification of whole-body 111In retention, expressed as a percentage of whole-body activity at 3 hr following injection, as an alternative method. The patient stood in front of the uncollimated gamma camera at a distance of 4 m and counts were collected over 2 min. The geometric mean was taken of posterior and anterior counts and compared with a 111In standard. The lower limit of the 95% confidence interval for whole-body retention in normals was 90%. Forty-five studies were performed on 33 patients with IBD. They were assessed in two groups, one to whom routine instructions for the collection of feces were given (Group A) but who did not always comply. The other group received oral and written instructions and were also monitored during the collection period (Group B) and reported full fecal collection. Although in Group A the correlation between fecal excretion and whole-body retention was good (r = 0.7, n = 32; p less than 0.001), in Group B the relationship between fecal excretion and whole-body retention was significantly better (r = 0.95, n = 18; p less than 0.001). On average, 111In whole-body retention was consistent with findings obtained during imaging: 111In excretion (100-whole-body retention) was 7.8% +/- 4.9% in 5 normal scans, 10% +/- 5.9% in 17 (+) scans, 22.3% +/- 8% in 20 (++) scans and 57% +/- 16% in 8 ( ) scans. We conclude that imaging is more sensitive than whole-body retention and fecal excretion in the detection of disease, but for quantification, whole-body retention is an accurate reliable alternative to fecal excretion.

Imaging of inflammation with indium-111 tropolonate labeled leukocytes.

Indium-111 tropolonate has recently been introduced as a new cell-labeling agent. It has the interesting property of labeling cells in plasma with high efficiency, and may therefore promote an improvement in viability of labeled cells. This paper describes our initial experience with In-111 tropolonate as a leukocyte label for abscess imaging. Pure populations of separated granulocytes, as well as crude leukocyte preparations, have been labeled. Of 101 studies performed, 51 were positive (no false positives) and 50 negatives, of which only two were false negatives. Localization in sites of inflammation was prominent and rapid. Of 36 positive studies, 27 were already positive at 40 min following injection and an additional nine at 3 hr. Of the other 15 positive studies, 11 were scanned for the first time at 3 hr, when they were positive. Granulocytes labeled with this agent in plasma showed minimal sequestration in lungs and liver, interpreted as indicating improved viability in comparison with cells displaying prolonged lung sequestration.

Quantitative scintigraphy in diagnosis and management of plantar fasciitis (calcaneal periostitis): concise communication.

We have found that Tc-99m methylene diphosphonate imaging of the heel is of diagnostic value in the "painful heel syndrome," permitting positive identification of the site of inflammation in cases where radiography is unhelpful. With this technique, tracer uptake in the heel is susceptible to quantification, allowing a serial and objective assessment of response to therapy.

Imaging of tumor in patients with indium-111-labeled biotin and streptavidin-conjugated antibodies: preliminary communication.

Tumor localization in patients has been achieved through the in vivo use of streptavidin and biotin. In these preliminary studies, the monoclonal antibody HMFG1 was conjugated with streptavidin and 1 mg was administered intravenously to each of 10 patients with documented squamous cell carcinoma of the lung. Two to 3 days later, 111In-labeled biotin was also administered intravenously. No evidence of toxicity was observed. Background radioactivity levels were reduced in liver (1% ID at 24 hr) and kidneys (2%) and in all other normal tissues and blood. Images of lung tumor were obtained in as little as 2 hr following administration of labeled biotin. In eight patients, tumor was detected with labeled biotin alone without the previous administration of streptavidin-conjugated antibody but in three of these patients, the images were improved with the prior administration of conjugated antibody. These results suggest that this approach may improve the tumor-to-normal tissue radioactivity ratios in radioimmunotargeting.

Intrahepatic kinetics of indium-111-labelled platelets.

The intrahepatic kinetics of 111indium-labelled platelets have been studied using dynamic gamma camera scintigraphy immediately following injection. Platelets labelled in saline with 111In-oxine or 111In-acetylacetonate underwent rapidly reversible hepatic sequestration, indicating that they were "activated". Platelets labelled in plasma with 111In-tropolonate, however, did not display this phenomenon. On the assumption that plasma-labelled platelets display a normal initial bio-distribution, mean intrahepatic platelet transit time, as a factor of the transit time of 99m-Tc labelled red cells, was 1.45 +/- SE 0.12 (n = 6), implying the normal presence of a small intrahepatic platelet pool. Unlike the liver, transit through the spleen was not sensitive to the labelling medium; thus the mean intrasplenic transit time of plasma-labelled platelets was 9.3 +/- SE 0.7 min (n = 10), and of saline-labelled platelets 9.5 +/- SE 0.3 min (n = 8).

Effect of amiodarone on left ventricular ejection and filling in hypertrophic cardiomyopathy as assessed by radionuclide angiography.

Left ventricular (LV) function at rest was assessed by radionuclide angiography in 30 patients with hypertrophic cardiomyopathy (HC) before and during treatment with amiodarone (600 to 800 mg for 1 week, 200 to 400 mg/day thereafter) for an initial maintenance period of 1 month in 30 patients and 6 months in 12 patients. The reproduciblity of the measurements was assessed by performing control studies within 24 hours in 13 patients and at 1 to 6 months in 6 patients, and 95% confidence limits for spontaneous change were determined. There was a significant decrease in heart rate at 1 month (from 67 +/- 9 vs 61 +/- 9 beats/min, p less than 0.004) with no further decrease at 6 months. Systemic blood pressure did not change. After amiodarone therapy, for each of the measurements of LV function except peak ejection rate, there was no mean change and the number of patients in whom the values increased and decreased by more than the 95% confidence limits were approximately equal. Peak ejection rate showed a significant decrease at 1 month, but this effect was not maintained at 6 months; 4 of 6 patients who showed a significant decrease at 1 month were reevaluated at 6 months, and in all 4 the values had returned to control levels. These findings suggest that the 95% confidence limits for spontaneous change were not wide enough and that chronic oral amiodarone therapy does not alter radionuclide indexes of LV function at rest in patients with hypertrophic cardiomyopathy.

Prognostic significance of radionuclide-assessed diastolic function in hypertrophic cardiomyopathy.

To evaluate the prognostic significance of diastolic function in hypertrophic cardiomyopathy (HC), technetium-99m gated equilibrium radionuclide angiography, acquired in list mode, was performed in 161 patients. Five diastolic indexes were calculated. During 3.0 +/- 1.9 years, 13 patients had disease-related deaths. With univariate analysis, these patients were younger (29 +/- 20 vs 42 +/- 16 years; p less than 0.05), had a higher incidence of syncope (p less than 0.025), dyspnea (p less than 0.001), reduced peak filling rate (2.9 +/- 0.9 vs 3.4 +/- 1.0 end-diastolic volume/s; p = 0.09) with increased relative filling volume during the rapid filling period (80 +/- 7 vs 75 +/- 12%; p = 0.06) and decreased atrial contribution (17 +/- 7 vs 22 +/- 11%; p = 0.07). Stepwise discriminant analysis revealed that young age at diagnosis, syncope at diagnosis, reduced peak ejection rate, positive family history, reduced peak filling rate, increased relative filling volume by peak filling rate and concentric left ventricular hypertrophy were the most statistically significant (p = 0.0001) predictors of disease-related death (sensitivity 92%, specificity 76%, accuracy 77%, positive predictive value 25%). Discriminant analysis excluding the diastolic indexes, however, showed similar predictability (sensitivity 92%, specificity 76%, accuracy 78%, positive predictive value 26%). To obtain more homogeneous groups for analysis, patients were classified as survivors (116) or electrically unstable (40), including sudden death, out-of-hospital ventricular fibrillation and nonsustained ventricular tachycardia during 48-hour ambulatory electrocardiography, and heart failure death or cardiac transplant (5).(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired left lower lobe ventilation in patients with cardiomegaly. An isotope study of mechanisms.

Reduced left lower lobe ventilation (V) in patients with enlarged hearts has been commonly observed on routine isotope ventilation-perfusion lung scanning, and there is evidence to show that this reduction is dependent on posture. Clinically, it may have a role in posture-dependent dyspnea and postoperative left lower lobe changes in cardiomegaly. Previous studies have shown improvement in left lower lobe V in the prone compared with the supine position. In 11 patients showing this phenomenon in krypton 81m V scanning, a mean relative reduction in V of 53 percent occurred at the left base. No significant change in perfusion or in the signal from preinjected technetium 99m macroaggregated albumin was observed between the two positions. No significant change in ventilatory turnover (measured with intravenous xenon 133) was seen either, suggesting that no air trapping takes place. By combining the data from the intravenous 133Xe (which gives the ratio, V/lung volume) and continuously inhaled 81mKr (which reflects regional V), an index of relative volume between the two sides was derived and shown to be significantly reduced at the left base on moving from the prone to supine positions (a mean reduction of 40 percent; p less than 0.02 by Wilcoxon signed rank test). Thus, the mechanism of postural left lower lobe hypoventilation in cardiomegaly is predominantly a regional loss of alveolar volume.

Platelet imaging of thromboembolism. Natural history of postoperative deep venous thrombosis and pulmonary embolism illustrated using the 111In-labelled platelet-specific monoclonal antibody, P256.

BACKGROUND: Deep venous thrombosis (DVT) and pulmonary thromboembolic disease are difficult to diagnose, particularly following surgery. This report demonstrates the use of 111In-labelled platelet-specific monoclonal antibody, P256 Fab', for the diagnosis and study of the time course of thromboembolic disease in a patient following total hip replacement. METHOD: One hundred micrograms of pentetic acid (DTPA)-P256 Fab' was labelled with 8 to 10 MBq of 111In chloride by incubation at room temperature for 15 min. After dilution in physiologic saline, the tracer was injected intravenously on the third and sixth days postoperatively. Imaging of the chest, pelvis, and legs was carried out at 24, 48 and 72 h following each injection. RESULTS: The first image four days after surgery demonstrated activity in the right heart which moved to the right pulmonary artery on the following day. Activity was seen in both femoral veins; on the left, this increased over two days, followed by a reduction on the seventh day after surgery, at which time new activity was seen in the right heart. After a further two days, this activity moved to the left pulmonary artery. The DVT was confirmed by venography and the pulmonary embolism (PE) by ventilation perfusion scan. CONCLUSIONS: 111Indium-labelled platelet-specific monoclonal antibody, P256 Fab', provides a technique for studying the natural history of thromboembolic disease and its treatment.

Elution of 111Indium from reticuloendothelial cells.

Measurement of isotope accumulation in an organ is often used to assess that organ's removal of blood cells labelled with the isotope. This technique is only valid if the isotope does not elute from the organ. Elution of 111In from the liver and spleen has been investigated in 14 subjects following intravenous injection of heat-damaged erythrocytes labelled with 111In. The elution rate from the spleen was found to be low, about 2% of the initial activity per day. The liver accumulated activity with respect to its initial uptake at a rate of about 5% per day. Bone marrow was not visualised except in two patients in whom it was identifiable in the initial scan.