Clinical Radiology (1990) 42~ 80-84
Review Radionuclides and the Gut Disease s of the gut follow the general rule that diagnosis is based upon anatomical localization of the site of disease, and an analysis of consequent disorder of function. In expert hands the modern versions of traditional radiological techniques are outstandingly good at anatomical localization, particularly when complemented by ultrasound and computed tomography. The contribution of traditional techniques to observing disorders of function has been confined to studies of motility and transit, often carrying a relatively high radiation burden. Radionuclide studies play a small part in anatomical localization of abnormalities and have the added advantage of being ideally suited to study disordered function. The necessary equipment is available widely and the radiation burden acceptably low. In clinical practice, the differentiation between the two types of tests is not always clear cut. For example, both selective angiography and red cell labelling tests can demonstrate the abnormal function of bleeding into the lumen. There is so much common ground and so many possible methods of investigation that it is important to evaluate the unique contributions of radionuclide studies in order to integrate them properly into schemes of investigation. Relatively infrequently one of the investigations will be carried out on a lactating mother which will require careful assessment of the radiation burden from her breast milk. Usually interruption is not essential (e.g. i~qn leucocytes); sometimes temporary interruption is necessary (e.g. 99Tcm erythrocytes); none of the tests described here requires cessation of breast feeding. The relevant guidance should be consulted (Mountford and Coakley, 1989). Some tests have been devised with considerable ingenuity which exceeds their practical applications. The present discussion will be concerned with the use of well established or highly promising tests in the investigation of well known clinical problems. DYSPHAGIA
Structural lesions are detected with high sensitivity by barium swallow and endoscopy (Ott, Wu and Gelfant, 1981). These techniques are less reliable in assessing dysmotility as a cause of dysphagia, and manometric assessment of oesophageal peristalsis has found little favour as an initial test in the United Kingdom. The passage of a 10 ml water bolus containing 20 MBq 99Tcmsulphur colloid can be recorded directly from a gamma camera and timed accurately. The technique is described in detail elsewhere (Channer and Virjee, 1985), and enables delay to be detected at all levels, e.g. in the upper oesophagus in Parkinson's disease or more generally in diabetic autonomic neuropathy. Inco-ordination of peristalsis is recognized by noting the bolus moving up and down in the oesophagus on prolonged observation, and in atonic dysfunction, e.g. systemic sclerosis, activity may remain in the oesophagus for up to 10 min, despite additional water drinks.
The test should be carried out only in cooperative patients who are able to swallow and are unlikely to vomit, and who have already had conventional studies of the oesophagus. In systemic sclerosis and diabetic autonomic neuropathy an abnormal test may be the first evidence of involvement. This high sensitivity may cause difficulties of interpretation in the symptom-free patient, and it is essential to relate the findings to the general clinical picture as well as the results of other tests. It is important to obtain accurate measurements by ensuring that each observation is made on a series of 'single' swallows in order to eliminate delay due to multiple swallows and intrinsic variations (Bartlett et al., 1987). The range of normality is shorter if the examination is done in the erect position (Sand et al., 1986). ABNORMAL GASTRIC EMPTYING SYNDROMES A small but significant proportion of patients who have had an operation for peptic ulcer have clinical syndromes that suggest early gastric emptying (dumping syndrome), less commonly diarrhoea, and occasionally food vomiting due to delayed emptying. The precise incidences vary with the different surgical techniques employed (Goligher et al., 1978). In this group of patients, symptoms are difficult to evaluate and the post-operative abnormalities may improve with time, so that it is important to have an objective measurement of gastric emptying. Vomiting and weight loss may be the first indications of diabetic gastro-paresis, whereas delayed gastric emptying associated with hiatus hernia may contribute to reflux oesophagitis (Donovan et al., 1977). Objective measurement of gastric emptying contributes to the diagnosis of these problems and also is important in evaluating operations for treating morbid obesity (Gannon et al., 1985). Gastric emptying is influenced by smoking, gravity, volume and calorific content of the meal and a variety of drugs. It is advisable for the patient to fast without smoking for 4 h; to omit drugs that influence gastric motility for 24 h; to sit the patient in front of the gamma camera and to standardize the volume and content of the meal. Several different meals have been proposed and most departments have their own particular favourite. One that is very reliable contains scrambled eggs labelled with 99Tcm sulphur colloid and water or 10% dextrose labelled with N3Indiumm. This combination allows study of solid and liquid phase, either at the same time or on successive days. A number of technical problems beset the collation and analysis of data, which must of course be standardized, and these are discussed in detail elsewhere (Harding and Donovan, 1988). In essence, data are recorded at frequent intervals from the moment the meal is begun until there is about 25% of it remaining in the stomach. Usually it is unnecessary to continue the investigation beyond 90 min. Some empty" ing will have occurred before the meal has been finished and it is possible to calculate the peak volume within the
RADIONUCLIDES AND THE GUT
stomach after the end of the meal. It is reduced after all gastric surgery, but many patients can tolerate marked reduction without developing a 'dumping' syndrome (Harding and Donovan, 1988). The simplest subsequent measure of gastric emptying is the T1/2 which is calculated, using semi-logarithmic paper, from the peak value to the 50% emptying value. It is considerably influenced by variations in the rate of emptying and other more complex measures have been put forward. For most clinical purposes, standardized use of the simplest technique is all that is necessary as there are many day-to-day variations in gastric emptying that cannot be allowed for and the significance of values outside the normal range varies among patients. The test is valuable for investigating individual symptomatic patients and for assessing the value of surgical treatment in different groups of patients. It is particularly useful in assessing operations that are designed specifically to change the pattern of gastic emptying. SYNDROMES ASSOCIATED W I T H REFLUX
Gastro-oesophageal The symptoms of this form of reflux include heartburn, regurgitation, dysphagia and occasionally anaemia, and a diagnosis can be made nearly always from a carefully taken history. Failure to respond to treatment or symptoms that mimic cardiac disease when there is known to be none, pose diagnostic problems that require further investigation with either barium swallow or endoscopy in the first place. Challenging the oesophageal mucosa with a perfusion of 0.1 N hydrochloric acid or monitoring the oesophageal pH for 24 h have been advocated as the ultimate tests but both of them are inconvenient and not carried out readily. Alternatively, after overnight fast, the erect patient drinks 10 MBq of 99Tcmsulphur colloid in 150 ml of 0.1 N hydrochloric acid and 150 ml of water. Subsequent images of the abdomen are taken to show activity in the oesophagus and, if none is present, a binder is applied to the abdomen and tightened in order to provoke reflux (Malmud and Fisher, 1982). The test is not used widely and is regarded by many as being unphysiological.
Duodeno-gastric Despite controversy about the effect of duodenal reflux on the gastric mucosa, it is well known that it occurs more often after Polya gastrectomy, less often after Bilroth I partial gastrectomy, vagotomy and pyloroplasty and least often after proximal gastric vagotomy (Thomas, 1988). This reflux is aggravated by biliary disease or cholecystectomy (Brough et al., 1984). There is no clear relationship between the severity of symptoms and the degree of reflux but if further surgery is planned to remedy the symptoms, it is logical to confirm the presence of reflux first, and its improvement later. The fasting patient is given 80 MBq 99Tcm p-butyl!mmonodiacetic acid (BIDA) intravenously and serial mlages of the upper abdomen are taken (Thomas et al., 1984). A gall bladder stimulant is then given (e.g. milk, Lundh test meal, intravenous cholecystokinin) and gall bladder emptying is recorded over the next 30 min. At the end of the investigation, 100 ml of l13In chloride is given
81
by mouth in order to mark the position of the stomach. A region of interest is defined around it so that fluctuations in activity within the stomach, due to reflux, can be identified. Difficulties may be encountered because of overlapping of the left lobe of the liver and of the upper jujenum. Many normal subjects have some reflux and it is important to determine the severity. It is tedious to calculate the volume of reflux, and moreover it may be both inaccurate and misleading. The two major determinants of the significance of reflux are the level to which it occurs in the stomach or even in the oesophagus occasionally, and its persistence. Both these parameters can be determined by simple inspection of serial images or of a time activity curve derived from a region of interest drawn round the stomach. Validation of such a simple assessment by comparison with computerized, normalized data and with bile salt content of the gastric juice indicated that scintigraphy detects reflux reliably. It is more accurate in quantifying the higher grades of reflux than the trivial and less significant degrees of reflux (Thomas et al., 1984; Houghton et al., 1986). Despite the technical difficulties and the intermittent nature of duodeno-gastric reflux, the test has an appealing simplicity because it is available wherever there is a gamma camera. It is particularly useful in assessing the role of the duodeno-gastric reflux in the aetiology of gastritis, oesophagitis, gastric ulcer, gastric cancer and post-gastrectomy symptoms, but there remains a regrettable lack of standardization for presenting the data. GASTRO-OESOPHAGEAL REFLUX IN
CHILDREN In children, this form of reflux is a common problem which is usually managed by simple clinical measures, without the need for radiological investigation. It may be suspected in the presence of copious vomiting, failure to thrive, anaemia, recurrent chest infections and following repair of tracheo-oesophageal fistula and atresia (Carty, 1989). Barium studies are usually the first radiological investigation in order to identify vascular rings, hiatus hernias, gastric volvulus and malrotation. Reflux may be demonstrated at this stage. The so-called 'milk scan' is indicated when (a) symptoms persist despite a negative barium meal, (b) reflux is a suspected cause of recurrent respiratory infections, (c) fluoroscopy is difficult, e.g. in mentally deficient children and children with Down's syndrome, (d) following repair of a tracheo-oesophageal fistula. Twenty-five MegaBequerels of 99Tcmsulphur colloid is mixed with 100 ml orange juice and given to the infant lying on its side on the gamma camera. This study is recorded for 4 min and after the feed has finished, a second feed without the radiolabel is given and the study is repeated. Activity over the oesophagus is estimated qualitatively by means of timeactivity curves and delayed scans up to 4 h are done to check whether there is activity in the lungs. ACUTE INTESTINAL BLEEDING The approach to the clinical management of acute gastro-intestinal bleeding is not uniform, and the place of
82
CLINICALRADIOLOGY
surgery, as well as the timing of operations, are open to debate. On the other hand, the aims of investigation are quite clearly to confirm the presence of bleeding and to locate its site. The combination of barium studies, endoscopy, and angiography is impressively successful in the diagnosis of the vast majority of patients with gastro-intestinal bleeding (Wright et al., 1980). However, these techniques are significantly less successful in detecting bleeding sites in the colon than elsewhere (Todd and Ford, 1979) and angiography and endoscopy have an additional difficulty because of the intermittent nature of bleeding, even when it is acute and severe. Finally, angiography is unsuccessful if the bleeding is venous or if there is barium in the gut (Slade, 1988). The positive applications of scintigraphy fall into two main groups. First, when endoscopy is contraindicated or inconclusive and, second, when the previous investigations have confirmed the presence of bleeding into the lumen but have not shown the site of bleeding. Colloid scanning is the most sensitive test for gastrointestinal bleeding but because its value is limited to the few minutes after intravenous injection, it is held by many to be a n impracticable test. Erythrocyte scanning is slightly less sensitive but much more sensitive than angiography. The most attractive technique is to sensitize the red cells by making an initial intravenous injection of stannous chloride and sodium pyrophosphate which form a complex with the red cell. One hour later 800 MBq 99Tcm pertechnetate are injected and are bound to the red cell complex. Images of the whole abdomen can be recorded immediately and at intervals, frequently at first and subsequently for as long as 24 h if needed. The ability to view the whole abdomen gives an important advantage over endoscopy and selective angiography. The main disadvantage of the technique is that the binding of the 99Tera is less than perfect and some unbound radionuclide is trapped in the stomach and excreted into the gut. This is usually identified readily and high degrees of specificity are recorded, with the ability to detect bleeding rates as low as 0.5 ml/min (Friedman et al., 1983). Blood causes increased bowel motility and may have moved to a more distal site by the time the next scan is taken. Usually it is possible to recognize this and not be misled about the site of bleeding. 111In labelling of red cells is now being developed and has the advantages that it has no gastrointestinal secretion if unbound, and scanning can be continued for up to 72 h because of the longer half-life of lllIn. Minimal recorded bleeding rates tend to be rather higher than with technetium. The use of arteriography and radionuclide imaging before laparotomy will depend upon the clinical circumstances. If arteriography is considered, it is often helpful to have a preliminary red blood cell scan to identify the site of bleeding so that the appropriate artery can be catheterized first. A positive scan indicates active bleeding. Scans frequently become positive after the first hour of the test and the radioactivity m a y have moved on from the site of bleeding, but correct localization is still possible in over 75% of cases (Winzelburg et al., 1982). Subsequent negative arteriography is well recognized in a small proportion and is ascribed to intermittent bleeding or a bleeding rate that is too slow to be detected arteriographically. On balance, the erythrocyte scan has more advan-
tages than alternative techniques, especially for detecting low rates of intermittent bleeding. There is some evidence to suggest that a positive scan is a reliable predictor of a tendency to re-bleed and an indicator of the need for more intensive clinical care (Robinson, 1986).
E C T O P I C GASTRIC M U C O S A In children and occasionally in adults, painless, often profuse rectal bleeding or chronic anaemia may raise the possibility of ectopic gastric mucosa within a Meckel's diverticulum. The appropriate investigation is serial imaging of the abdomen for about 45 min, following an intravenous injection of 99Tcm pertechnetate. Eutopic gastric mucosa becomes identifiable increasingly well over the first 20 min and the ectopic mucosa should do so at the same time. Usually it lies in the pelvis, close to the bladder which will contain radioactive urine because of renal excretion of 99Tcm. Therefore at the end of the investigation a post-micturition view and a posterior view are recommended in order to ensure there is no ectopic mucosa deep in the pelvis behind the fundus of the bladder. Active bleeding is not necessary for the'scan to be positive but it is important to realize that the test is for ectopic gastric mucosa and not for Meckel's diverticulum, which may of course not contain any gastric mucosa. A sensitivity of 95% has been reported (Treeves & Grand, 1985) but not attained in all series. In order to reduce the number of false negatives, it has been suggested that the uptake and retention of the radioactive substance by the gastric mucosa can be enhanced respectively by giving pentagastrin and cimetidine before the test but this is not generally advocated (Carry, 1988). The same technique can be used to identify ectopic mucosa elsewhere, notably in the oesophagus--saliva containing 99Tem should be absorbed in cotton wool plegets--and remnants of acid secreting mucosa after partial gastrectomy. False positive results may result from activity in the ureter, activity in the bowel lumen after secretion by the stomach, normal uterus in adult females, intussusception, focal acute inflammation. Ectopic gastric mucosa in other sites may be shown by the same technique, e.g. oesophagus, enteric duplications, duplication cysts, gastrogenic cysts (Merrick, 1984).
I N F L A M M A T O R Y DISEASE OF THE BOWEL
The use of 11~In leucocytes is a major, relatively recent advance in the investigation of inflammatory disease in the bowel and elsewhere (McAfee and Thakur 1976; Segal et al., 1981; Buxton-Thomas et al., 1984). The essence of the technique is that the indium is linked with a chelating agent to form a complex that penetrates the leucocyte membranes. The complex then dissociates and the labelling of the cell is stable. The leucocytes are very sensitive when being handled and there are still some problems that lead to poor labelling and impaired leucocyte function. There is still not universal agreement on the choice between oxine or tropolone in plasma as the chelating agent of choice. If the cells are damaged during labelling, 'clumping' of leucocytes in the lung may be seen (Coleman et aL, 1980) and consequent delay in lung transit may lead to poor quality images.
RADIONUCLIDES AND THE GUT
83
Very rarely, neutropenia causes a problem because too few leucocytes are available for labelling, and this can be overcome by using donor cells (Anstall and Coleman, 1982). The diagnosis of clinically suspected inflammatory bowel disease usually rests on the results of radiological and endoscopic examinations. Indium scintigraphy is often used at a later stage in the management of these patients, though it has a high sensitivity in detecting inflammatory bowel disease (Gainey and McDougall, 1984).
ulceration. It was proposed for detecting Crohn's disease and ulcerative colitis because mucosal ulceration occurs in these diseases and a number of favourable reports have been made (Dawson et al., 1985; Vasquez et al., 1987). However, there are also critical accounts of the usefulness of the technique based on poor correlation with other tests, including ~11In leucocyte scanning; hazards of purgation in seriously ill patients; and poor acceptance by patients of the need for several scans (Crama-Bohbouth et al., 1988). The labelled leucocyte techniques are generally regarded as most useful.
The Activity of Disease
RADIOIMMUNODETECTION OF TUMOURS
Indium leucocytes accumulate in regions of active Crohn's disease or ulcerative colitis but they do not do so when the disease is quiescent. There may be a role for the technique in the investigation of acute toxic megacolon when both barium and endoscopic investigations are absolutely contra-indicated. It is non-specific and therefore will not distinguish between the possible causes of such a condition. Determining the Extent of Disease The technique has a sensitivity of over 80% and a specificity of over 90% (Gainey and McDougall, 1984) and the results compare very favourably with barium studies. Thus they offer a relatively simple low radiation technique for monitoring the progress of established disease in response to treatment. Investigating the Complications of Inflammatory Bowel Disease Abscesses are detected safely with high accuracy whether they are the result of acute inflammatory bowel disease or of post-operative sub-hepatic and sub-phrenic abscesses. False-positives may result from accumulation of leucocytes at the sites of drainage tubes, catheters and intramuscular injections; from swallowed activity from sputum; accessory spleen (Coleman et al., 1980) and infarcted bowel (Gray et al., 1981). If there is no clinical or plain radiographic evidence of the site of a suspected abscess, leucocyte scintigraphy is an ideal preliminary to localize the abnormality before ultrasound or CT is used to pinpoint the lesion and to aid biopsy and drainage. The radioactivity accumulated in inflammatory bowel disease passes rapidly into the lumen of the bowel and serial images over 24 h must be interpreted with great care so as to avoid over-estimating the extent of disease. Techniques have been developed to estimate the percentage of injected radioactivity that can be recovered from the stools in 48 h and there is quite a good correlation with disease activity assessed by other methods (BuxtonThomas et al., 1984). ~lqn-leucocyte scanning has effectively replaced the non-specific 67Ga scanning, but positive uptake has been recorded in metastasis from adenocarcinoma of the prostate and lymphoma (Slade, 1988). The enthusiasm for leucocyte scanning is not mirrored for 99Tcm sucralphate scanning. Sucralphate is an aluminium salt of poly sulphated sucrose which is effective in treating peptic ulcer because it binds at the site ofmucosal
It is well known that a variety of tumours express antigens. Strenuous attempts have been made to produce specific antibodies to some of these antigens, using single clones of lymphocyte-myeloma hybrid cells; and then to label the antibodies with a suitable radionuclide. The potential clinical applications include both localization and treatment of the tumours (Hammersmith Oncology Group, 1984; Begent and Jewkes, 1986; Britton and Granowska, 1988). Carcinoembryonic antigen (CEA) is expressed by colorectal carcinomas and much experience is available of using its antibody labelled with 131Iand 1231.The quality of the images is only moderately good because of the relatively low uptake by the tumour and complicated subtraction techniques have been devised to improve the image quality. The most promising display techniques take account of temporal changes in activity over serial images, so that significant changes that identify tumour sites are given an appropriate colour code on the final image (Granowska et al., 1988). The technique does not supplant conventional methods of detecting primary tumours and is unsuitable for screening because it is not tumour specific and involves the injection of a foreign protein. Indeed a negative intradermal test is an essential prerequisite for continuing the investigation. Its application in staging colorectal carcinoma is limited because pelvic lymph nodes may trap the antigen cells even when there is no tumour. The most promising use is in detecting recurrence after primary surgical treatment. It is well known that fibrous tissue in the pelvis can mimic carcinoma on computed tomography and a radioimmuno scan enables the differentiation. For biophysical reasons 123I is a more satisfactory label than 1311and recently Ill Inanti CEA antibodies have been recommended because of their greater stability and improved pharmacokinetics. Even so, their lack of tumour specificity cause liver metastasis to be overlooked, and false positives to arise from inflammatory bowel disease (Bares et al., 1989). CONCLUSION Radionuclide imaging is an indispensable part of the diagnosis and management of bowel disorders. The tests require little or no preliminary preparation and can be done on out-patients. The investigations described here are not exhaustive and do not include well established radionuclide techniques that are laboratory based and usually outside the scope of diagnostic radiology. The imaging techniques should be available to all radiologists who aspire to higher accuracy and greater effectiveness.
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CLINICAL RADIOLOGY
REFERENCES
Anstall, HB & Coleman, RE (1982). Donor leucocyte imaging in granulocytopaeniac patients with suspected abscesses. Journal of Nuclear Medicine, 23, 319-321. Bares, R, Fass J, Truong, S, Buell, U & Schlumpelick, V (1989). Radioimmunoscintigraphy with 111inlabelled monoclonal antibody fragments against CEA. Nuclear Medicine Communications, 10, 624-641. Bartlett, RJV, Parkin, A, Ware, FW, Riley, A & Robinson, PJA (1987). Reproducibility of oesophageal transit studies. Nuclear Medicine Communications, 8, 317 326. Begent, RHJ & Jewkes, RF (1986). Radiotabelled antibodies for imaging gastrointestinal tumours. In Nuclear Gastroenterology, ed. Robinson, PJA, pp. 145-156. Churchill Livingstone, Edinburgh. Britton, KE & Granowska, M (1988). In Nuclear Medicine: Applications to Surgery, eds Davies, ER & Thomas, WEG, pp. 300-311. Castle House Publications, Tunbridge Wells. Brough, WA, Taylor, TV & Torrance, HB (1984). Surgical factors in influencing duodeno-gastric reflux. British Journal of Surgery, 71, 770-773. Buxton-Thomas, MS, Dickinson, RJ, Maltby, P, Hunter, JO & Wraight, EP (1984), An evaluation of indium scintigraphy in patients with active inflammatory bowel disease. Gut, 25, 1372-1375. Carty, H (1988). Specific problems in children. In Nuclear Medicine: Applications to Surgery, eds. Davies, ER & Thomas, WEG, pp. 270 299. Castle House Publications, Tunbridge Wells. Channer, KS & Virjee, JP (1985). Oesophageal function tests--are they of value. Clinical Radiology, 36, 493-496. Coleman, RE, Black, RE, Welch, MD, Maxwell, JG (1980). Indium-111 labelled leukocytes in the evaluation of suspected abdominal abscesses. American Journal of Surgery, 139, 99-103. Crama-Bohbouth, GE, Arndt, JW, Pena, AS, Blok, D, Verspaget, HW, Weterman, IT, Lamers, CBHW & Pauwe, EKT (1988). Is radiolabelled sucralphate scintigraphy of any use in the diagnosis of inflammatory bowel disease. Nuclear Medicine Communications, 9, 591-595. Dawson, D J, Khan, AN, Miller, V, Ratcliffe, JF & Shreeve, DR (1985). Detection of inflammatory bowel disease in adults and children: evaluation of a new isotope technique. British Medical Journal, 291, 1227 1230. Donovan, IA, Harding, LK, Keighley, MRB, Griffin, DW & Collis JL (1977). Abnormalities of gastric emptying and pyloric reflux in uncomplicated hiatus hernia. British Journal of Surgery, 64, 847848. Friedman, HI, Hitles, SV & Whitley, PJ (1983). Use of technetium labelled autologous red blood cells in detection of gastro-intestinal bleeding. Surgery, Gynaecology and Obstetrics, 156, 449 452. Gainey, MA & McDougall, IR (1984). Diagnosis of acute inflammatory conditions in children and adolescents using Indium- 111 oxine white blood cells. Clinical Nuclear Medicine, 9, 71-74. Gannon, MX, Pears, D J, Chandler, ST, Fielding, JWL & Baddeley, RM (1985). The effect of gastric partitioning on gastric emptying in morbidly obese patients. British Journal of Surgery, 72, 952-954. Goligher, JC, Hill, GL, Kenny, TE & Nutter, E (1978). Proximal gastric vagotomy without drainage for duodenal ulcer: results after 5-8 years. British Journal of Surgery, 65~ 145-151. Granowska, M., Nimmou, CC, Britton, KE, Crowther, A, Mather, SJ, Slevin, ML & Shepherd, JH (1988). Kinetic analysis and probability mapping applied to the detection of ovarian cancer by radioimmunoscintigraphy. Journal of Nuclear Medicine, 29, 599-607. Gray, HW, Cuthbert, I & Richards, JR (1981). Clinical imaging with Indium-111 leucocytes: uptake in bowel infarction. Journal of Nuclear Medicine, 22, 701-702. Hammersmith Oncology Group (1984). Antibody guided irradiation of malignant lesions. Lancet, i, 1441-1443.
Harding, LK & Donovan, IA (1988). Gastric emptying: gastro. oesophageal reflux. In Nuclear Medicine: Application's to Surgery, eds Davies, ER & Thomas, WEG, pp. 42-51. Castle House Publications, Tunbridge Wells. Houghton, PWJ, Mortensen, NJMcC, Thomas, WEG, Cooper, M J, Morgan, AP & Davies, ER (1986). Intragastric bile acids anti scintigraphy in the assessment of duodeno-gastric reflux. British Journal of Surgery, 73, 292 294. McAfee, JG & Thakur, ML (1976). Survey of radioactive agents for in vitro labelling of phagocytic leukocytes. Journal of Nuclear Medicine, 17, 480-492. Malmud, LS & Fisher, RS (1982). Radionuclide studies of oesophageal transit and gastric oesophageal reflux. Seminars in Nuclear Medicine, 12, 156-172. Merrick, MV (1984). The gastrointestinal tract. In Essentials of NuclearMedicine, Ed. Merrick, MV, pp. 203-223. Churchill Livingstone, Edinburgh. Mountford, PJ & Coakley AJ (1989). A review of the secretion of radioactivity in breast milk. Nuclear Medicine Communications, 10, 15-27. Mountford, PJ & Harding, LK (1989). Breast milk--still more data required. Editorial, Nuclear Medicine Communications, 10, 777-778. Ott, DJ, Wu, WC & Gelfant, DW (1981). Efficacy of radiology of the oesophagus for the evaluation of dysphagia. Gastrointestinal Radiology, 6, 109-110. Robinson, PJA (1986). Scintigraphy in gastrointestinal bleeding. In Nuclear Gastroenterology, Ed. Robinson, PJA pp. 127-144. Churchill Livingstone, Edinburgh. Sand, A, Ham, HR & Piepsz, A (1986). Oesophageal transit patterns in healthy subjects. Nuclear Medicine Communications, 7, 741-745. Segal, AW, Ensell, J, Munro, JD & Sarner, M (1981). Indium-Ill tagged leucocytes in the diagnosis of inflammatory bowel disease. Lancet, ii, 230-232. Slade, R (1988). Blood cell labelling techniques. In Nuclear Medicine: Applications to Surgery, eds Davies, ER & Thomas, WEG. pp. 208218. Castle House Publications, Tunbridge Wells. Thomas, WEG (1988). Duodeno-gastric reflux. In Nuclear Medicine: Applications to Surgery, eds Davies, ER & Thomas, WEG. pp. 52 61. Castle House Publications, Tunbridge Wells. Thomas, WEG, Cooper, M J, Mortensen, NJMcC, Davies, ER & Burton, P (1984). The clinical assessment of duodenogastric reflux by scintigraphy and its relation to histological changes in gastric mucosa. Scandinavian Journal of Gastroenterology, 19 (Suppl. 92), 195-199. Todd, GJ & Ford, KA (1979). Lower gastro intestinal bleeding with negative or inconclusive radiographic studies. American Journal of Surgery, 138, 627-631. Treeves, ST & Grand, R (1985). Meckel's diverticulum. In Paediatric Nuclear Medicine, pp. 179-189. Springer-Verlag, New York. Vasquez, TE, Pretorius, HT & Greenspan, G (1987). Radiolabelled sucralfate: a review of clinical efficacy. Nuclear Medicine Communications, 8, 327-334. Winzelburg, GG, McKusick, KA, Froelich, JW, Callahan, RJ & Strauss, HW (1982). Detection of gastrointestinal bleeding with TC 99m labelled red blood cells. Seminars in Nuclear Medicine, 12, 139-146. Wright, HK, Pelliccia, O, Higgins, EF, Screenivas, V & Gupta, A (1980). Controlled semielective segmental resection for massive colonic haemorrhage. American Journal of Surgery, 139, 538-539. E. R. D A V I E S University D e p a r t m e n t o f Radiodiagnosis R o y a l Infirmary Bristol B S 2 8 8 H W
Review Radionuclides and the Gut Disease s of the gut follow the general rule that diagnosis is based upon anatomical localization of the site of disease, and an analysis of consequent disorder of function. In expert hands the modern versions of traditional radiological techniques are outstandingly good at anatomical localization, particularly when complemented by ultrasound and computed tomography. The contribution of traditional techniques to observing disorders of function has been confined to studies of motility and transit, often carrying a relatively high radiation burden. Radionuclide studies play a small part in anatomical localization of abnormalities and have the added advantage of being ideally suited to study disordered function. The necessary equipment is available widely and the radiation burden acceptably low. In clinical practice, the differentiation between the two types of tests is not always clear cut. For example, both selective angiography and red cell labelling tests can demonstrate the abnormal function of bleeding into the lumen. There is so much common ground and so many possible methods of investigation that it is important to evaluate the unique contributions of radionuclide studies in order to integrate them properly into schemes of investigation. Relatively infrequently one of the investigations will be carried out on a lactating mother which will require careful assessment of the radiation burden from her breast milk. Usually interruption is not essential (e.g. i~qn leucocytes); sometimes temporary interruption is necessary (e.g. 99Tcm erythrocytes); none of the tests described here requires cessation of breast feeding. The relevant guidance should be consulted (Mountford and Coakley, 1989). Some tests have been devised with considerable ingenuity which exceeds their practical applications. The present discussion will be concerned with the use of well established or highly promising tests in the investigation of well known clinical problems. DYSPHAGIA
Structural lesions are detected with high sensitivity by barium swallow and endoscopy (Ott, Wu and Gelfant, 1981). These techniques are less reliable in assessing dysmotility as a cause of dysphagia, and manometric assessment of oesophageal peristalsis has found little favour as an initial test in the United Kingdom. The passage of a 10 ml water bolus containing 20 MBq 99Tcmsulphur colloid can be recorded directly from a gamma camera and timed accurately. The technique is described in detail elsewhere (Channer and Virjee, 1985), and enables delay to be detected at all levels, e.g. in the upper oesophagus in Parkinson's disease or more generally in diabetic autonomic neuropathy. Inco-ordination of peristalsis is recognized by noting the bolus moving up and down in the oesophagus on prolonged observation, and in atonic dysfunction, e.g. systemic sclerosis, activity may remain in the oesophagus for up to 10 min, despite additional water drinks.
The test should be carried out only in cooperative patients who are able to swallow and are unlikely to vomit, and who have already had conventional studies of the oesophagus. In systemic sclerosis and diabetic autonomic neuropathy an abnormal test may be the first evidence of involvement. This high sensitivity may cause difficulties of interpretation in the symptom-free patient, and it is essential to relate the findings to the general clinical picture as well as the results of other tests. It is important to obtain accurate measurements by ensuring that each observation is made on a series of 'single' swallows in order to eliminate delay due to multiple swallows and intrinsic variations (Bartlett et al., 1987). The range of normality is shorter if the examination is done in the erect position (Sand et al., 1986). ABNORMAL GASTRIC EMPTYING SYNDROMES A small but significant proportion of patients who have had an operation for peptic ulcer have clinical syndromes that suggest early gastric emptying (dumping syndrome), less commonly diarrhoea, and occasionally food vomiting due to delayed emptying. The precise incidences vary with the different surgical techniques employed (Goligher et al., 1978). In this group of patients, symptoms are difficult to evaluate and the post-operative abnormalities may improve with time, so that it is important to have an objective measurement of gastric emptying. Vomiting and weight loss may be the first indications of diabetic gastro-paresis, whereas delayed gastric emptying associated with hiatus hernia may contribute to reflux oesophagitis (Donovan et al., 1977). Objective measurement of gastric emptying contributes to the diagnosis of these problems and also is important in evaluating operations for treating morbid obesity (Gannon et al., 1985). Gastric emptying is influenced by smoking, gravity, volume and calorific content of the meal and a variety of drugs. It is advisable for the patient to fast without smoking for 4 h; to omit drugs that influence gastric motility for 24 h; to sit the patient in front of the gamma camera and to standardize the volume and content of the meal. Several different meals have been proposed and most departments have their own particular favourite. One that is very reliable contains scrambled eggs labelled with 99Tcm sulphur colloid and water or 10% dextrose labelled with N3Indiumm. This combination allows study of solid and liquid phase, either at the same time or on successive days. A number of technical problems beset the collation and analysis of data, which must of course be standardized, and these are discussed in detail elsewhere (Harding and Donovan, 1988). In essence, data are recorded at frequent intervals from the moment the meal is begun until there is about 25% of it remaining in the stomach. Usually it is unnecessary to continue the investigation beyond 90 min. Some empty" ing will have occurred before the meal has been finished and it is possible to calculate the peak volume within the
RADIONUCLIDES AND THE GUT
stomach after the end of the meal. It is reduced after all gastric surgery, but many patients can tolerate marked reduction without developing a 'dumping' syndrome (Harding and Donovan, 1988). The simplest subsequent measure of gastric emptying is the T1/2 which is calculated, using semi-logarithmic paper, from the peak value to the 50% emptying value. It is considerably influenced by variations in the rate of emptying and other more complex measures have been put forward. For most clinical purposes, standardized use of the simplest technique is all that is necessary as there are many day-to-day variations in gastric emptying that cannot be allowed for and the significance of values outside the normal range varies among patients. The test is valuable for investigating individual symptomatic patients and for assessing the value of surgical treatment in different groups of patients. It is particularly useful in assessing operations that are designed specifically to change the pattern of gastic emptying. SYNDROMES ASSOCIATED W I T H REFLUX
Gastro-oesophageal The symptoms of this form of reflux include heartburn, regurgitation, dysphagia and occasionally anaemia, and a diagnosis can be made nearly always from a carefully taken history. Failure to respond to treatment or symptoms that mimic cardiac disease when there is known to be none, pose diagnostic problems that require further investigation with either barium swallow or endoscopy in the first place. Challenging the oesophageal mucosa with a perfusion of 0.1 N hydrochloric acid or monitoring the oesophageal pH for 24 h have been advocated as the ultimate tests but both of them are inconvenient and not carried out readily. Alternatively, after overnight fast, the erect patient drinks 10 MBq of 99Tcmsulphur colloid in 150 ml of 0.1 N hydrochloric acid and 150 ml of water. Subsequent images of the abdomen are taken to show activity in the oesophagus and, if none is present, a binder is applied to the abdomen and tightened in order to provoke reflux (Malmud and Fisher, 1982). The test is not used widely and is regarded by many as being unphysiological.
Duodeno-gastric Despite controversy about the effect of duodenal reflux on the gastric mucosa, it is well known that it occurs more often after Polya gastrectomy, less often after Bilroth I partial gastrectomy, vagotomy and pyloroplasty and least often after proximal gastric vagotomy (Thomas, 1988). This reflux is aggravated by biliary disease or cholecystectomy (Brough et al., 1984). There is no clear relationship between the severity of symptoms and the degree of reflux but if further surgery is planned to remedy the symptoms, it is logical to confirm the presence of reflux first, and its improvement later. The fasting patient is given 80 MBq 99Tcm p-butyl!mmonodiacetic acid (BIDA) intravenously and serial mlages of the upper abdomen are taken (Thomas et al., 1984). A gall bladder stimulant is then given (e.g. milk, Lundh test meal, intravenous cholecystokinin) and gall bladder emptying is recorded over the next 30 min. At the end of the investigation, 100 ml of l13In chloride is given
81
by mouth in order to mark the position of the stomach. A region of interest is defined around it so that fluctuations in activity within the stomach, due to reflux, can be identified. Difficulties may be encountered because of overlapping of the left lobe of the liver and of the upper jujenum. Many normal subjects have some reflux and it is important to determine the severity. It is tedious to calculate the volume of reflux, and moreover it may be both inaccurate and misleading. The two major determinants of the significance of reflux are the level to which it occurs in the stomach or even in the oesophagus occasionally, and its persistence. Both these parameters can be determined by simple inspection of serial images or of a time activity curve derived from a region of interest drawn round the stomach. Validation of such a simple assessment by comparison with computerized, normalized data and with bile salt content of the gastric juice indicated that scintigraphy detects reflux reliably. It is more accurate in quantifying the higher grades of reflux than the trivial and less significant degrees of reflux (Thomas et al., 1984; Houghton et al., 1986). Despite the technical difficulties and the intermittent nature of duodeno-gastric reflux, the test has an appealing simplicity because it is available wherever there is a gamma camera. It is particularly useful in assessing the role of the duodeno-gastric reflux in the aetiology of gastritis, oesophagitis, gastric ulcer, gastric cancer and post-gastrectomy symptoms, but there remains a regrettable lack of standardization for presenting the data. GASTRO-OESOPHAGEAL REFLUX IN
CHILDREN In children, this form of reflux is a common problem which is usually managed by simple clinical measures, without the need for radiological investigation. It may be suspected in the presence of copious vomiting, failure to thrive, anaemia, recurrent chest infections and following repair of tracheo-oesophageal fistula and atresia (Carty, 1989). Barium studies are usually the first radiological investigation in order to identify vascular rings, hiatus hernias, gastric volvulus and malrotation. Reflux may be demonstrated at this stage. The so-called 'milk scan' is indicated when (a) symptoms persist despite a negative barium meal, (b) reflux is a suspected cause of recurrent respiratory infections, (c) fluoroscopy is difficult, e.g. in mentally deficient children and children with Down's syndrome, (d) following repair of a tracheo-oesophageal fistula. Twenty-five MegaBequerels of 99Tcmsulphur colloid is mixed with 100 ml orange juice and given to the infant lying on its side on the gamma camera. This study is recorded for 4 min and after the feed has finished, a second feed without the radiolabel is given and the study is repeated. Activity over the oesophagus is estimated qualitatively by means of timeactivity curves and delayed scans up to 4 h are done to check whether there is activity in the lungs. ACUTE INTESTINAL BLEEDING The approach to the clinical management of acute gastro-intestinal bleeding is not uniform, and the place of
82
CLINICALRADIOLOGY
surgery, as well as the timing of operations, are open to debate. On the other hand, the aims of investigation are quite clearly to confirm the presence of bleeding and to locate its site. The combination of barium studies, endoscopy, and angiography is impressively successful in the diagnosis of the vast majority of patients with gastro-intestinal bleeding (Wright et al., 1980). However, these techniques are significantly less successful in detecting bleeding sites in the colon than elsewhere (Todd and Ford, 1979) and angiography and endoscopy have an additional difficulty because of the intermittent nature of bleeding, even when it is acute and severe. Finally, angiography is unsuccessful if the bleeding is venous or if there is barium in the gut (Slade, 1988). The positive applications of scintigraphy fall into two main groups. First, when endoscopy is contraindicated or inconclusive and, second, when the previous investigations have confirmed the presence of bleeding into the lumen but have not shown the site of bleeding. Colloid scanning is the most sensitive test for gastrointestinal bleeding but because its value is limited to the few minutes after intravenous injection, it is held by many to be a n impracticable test. Erythrocyte scanning is slightly less sensitive but much more sensitive than angiography. The most attractive technique is to sensitize the red cells by making an initial intravenous injection of stannous chloride and sodium pyrophosphate which form a complex with the red cell. One hour later 800 MBq 99Tcm pertechnetate are injected and are bound to the red cell complex. Images of the whole abdomen can be recorded immediately and at intervals, frequently at first and subsequently for as long as 24 h if needed. The ability to view the whole abdomen gives an important advantage over endoscopy and selective angiography. The main disadvantage of the technique is that the binding of the 99Tera is less than perfect and some unbound radionuclide is trapped in the stomach and excreted into the gut. This is usually identified readily and high degrees of specificity are recorded, with the ability to detect bleeding rates as low as 0.5 ml/min (Friedman et al., 1983). Blood causes increased bowel motility and may have moved to a more distal site by the time the next scan is taken. Usually it is possible to recognize this and not be misled about the site of bleeding. 111In labelling of red cells is now being developed and has the advantages that it has no gastrointestinal secretion if unbound, and scanning can be continued for up to 72 h because of the longer half-life of lllIn. Minimal recorded bleeding rates tend to be rather higher than with technetium. The use of arteriography and radionuclide imaging before laparotomy will depend upon the clinical circumstances. If arteriography is considered, it is often helpful to have a preliminary red blood cell scan to identify the site of bleeding so that the appropriate artery can be catheterized first. A positive scan indicates active bleeding. Scans frequently become positive after the first hour of the test and the radioactivity m a y have moved on from the site of bleeding, but correct localization is still possible in over 75% of cases (Winzelburg et al., 1982). Subsequent negative arteriography is well recognized in a small proportion and is ascribed to intermittent bleeding or a bleeding rate that is too slow to be detected arteriographically. On balance, the erythrocyte scan has more advan-
tages than alternative techniques, especially for detecting low rates of intermittent bleeding. There is some evidence to suggest that a positive scan is a reliable predictor of a tendency to re-bleed and an indicator of the need for more intensive clinical care (Robinson, 1986).
E C T O P I C GASTRIC M U C O S A In children and occasionally in adults, painless, often profuse rectal bleeding or chronic anaemia may raise the possibility of ectopic gastric mucosa within a Meckel's diverticulum. The appropriate investigation is serial imaging of the abdomen for about 45 min, following an intravenous injection of 99Tcm pertechnetate. Eutopic gastric mucosa becomes identifiable increasingly well over the first 20 min and the ectopic mucosa should do so at the same time. Usually it lies in the pelvis, close to the bladder which will contain radioactive urine because of renal excretion of 99Tcm. Therefore at the end of the investigation a post-micturition view and a posterior view are recommended in order to ensure there is no ectopic mucosa deep in the pelvis behind the fundus of the bladder. Active bleeding is not necessary for the'scan to be positive but it is important to realize that the test is for ectopic gastric mucosa and not for Meckel's diverticulum, which may of course not contain any gastric mucosa. A sensitivity of 95% has been reported (Treeves & Grand, 1985) but not attained in all series. In order to reduce the number of false negatives, it has been suggested that the uptake and retention of the radioactive substance by the gastric mucosa can be enhanced respectively by giving pentagastrin and cimetidine before the test but this is not generally advocated (Carry, 1988). The same technique can be used to identify ectopic mucosa elsewhere, notably in the oesophagus--saliva containing 99Tem should be absorbed in cotton wool plegets--and remnants of acid secreting mucosa after partial gastrectomy. False positive results may result from activity in the ureter, activity in the bowel lumen after secretion by the stomach, normal uterus in adult females, intussusception, focal acute inflammation. Ectopic gastric mucosa in other sites may be shown by the same technique, e.g. oesophagus, enteric duplications, duplication cysts, gastrogenic cysts (Merrick, 1984).
I N F L A M M A T O R Y DISEASE OF THE BOWEL
The use of 11~In leucocytes is a major, relatively recent advance in the investigation of inflammatory disease in the bowel and elsewhere (McAfee and Thakur 1976; Segal et al., 1981; Buxton-Thomas et al., 1984). The essence of the technique is that the indium is linked with a chelating agent to form a complex that penetrates the leucocyte membranes. The complex then dissociates and the labelling of the cell is stable. The leucocytes are very sensitive when being handled and there are still some problems that lead to poor labelling and impaired leucocyte function. There is still not universal agreement on the choice between oxine or tropolone in plasma as the chelating agent of choice. If the cells are damaged during labelling, 'clumping' of leucocytes in the lung may be seen (Coleman et aL, 1980) and consequent delay in lung transit may lead to poor quality images.
RADIONUCLIDES AND THE GUT
83
Very rarely, neutropenia causes a problem because too few leucocytes are available for labelling, and this can be overcome by using donor cells (Anstall and Coleman, 1982). The diagnosis of clinically suspected inflammatory bowel disease usually rests on the results of radiological and endoscopic examinations. Indium scintigraphy is often used at a later stage in the management of these patients, though it has a high sensitivity in detecting inflammatory bowel disease (Gainey and McDougall, 1984).
ulceration. It was proposed for detecting Crohn's disease and ulcerative colitis because mucosal ulceration occurs in these diseases and a number of favourable reports have been made (Dawson et al., 1985; Vasquez et al., 1987). However, there are also critical accounts of the usefulness of the technique based on poor correlation with other tests, including ~11In leucocyte scanning; hazards of purgation in seriously ill patients; and poor acceptance by patients of the need for several scans (Crama-Bohbouth et al., 1988). The labelled leucocyte techniques are generally regarded as most useful.
The Activity of Disease
RADIOIMMUNODETECTION OF TUMOURS
Indium leucocytes accumulate in regions of active Crohn's disease or ulcerative colitis but they do not do so when the disease is quiescent. There may be a role for the technique in the investigation of acute toxic megacolon when both barium and endoscopic investigations are absolutely contra-indicated. It is non-specific and therefore will not distinguish between the possible causes of such a condition. Determining the Extent of Disease The technique has a sensitivity of over 80% and a specificity of over 90% (Gainey and McDougall, 1984) and the results compare very favourably with barium studies. Thus they offer a relatively simple low radiation technique for monitoring the progress of established disease in response to treatment. Investigating the Complications of Inflammatory Bowel Disease Abscesses are detected safely with high accuracy whether they are the result of acute inflammatory bowel disease or of post-operative sub-hepatic and sub-phrenic abscesses. False-positives may result from accumulation of leucocytes at the sites of drainage tubes, catheters and intramuscular injections; from swallowed activity from sputum; accessory spleen (Coleman et al., 1980) and infarcted bowel (Gray et al., 1981). If there is no clinical or plain radiographic evidence of the site of a suspected abscess, leucocyte scintigraphy is an ideal preliminary to localize the abnormality before ultrasound or CT is used to pinpoint the lesion and to aid biopsy and drainage. The radioactivity accumulated in inflammatory bowel disease passes rapidly into the lumen of the bowel and serial images over 24 h must be interpreted with great care so as to avoid over-estimating the extent of disease. Techniques have been developed to estimate the percentage of injected radioactivity that can be recovered from the stools in 48 h and there is quite a good correlation with disease activity assessed by other methods (BuxtonThomas et al., 1984). ~lqn-leucocyte scanning has effectively replaced the non-specific 67Ga scanning, but positive uptake has been recorded in metastasis from adenocarcinoma of the prostate and lymphoma (Slade, 1988). The enthusiasm for leucocyte scanning is not mirrored for 99Tcm sucralphate scanning. Sucralphate is an aluminium salt of poly sulphated sucrose which is effective in treating peptic ulcer because it binds at the site ofmucosal
It is well known that a variety of tumours express antigens. Strenuous attempts have been made to produce specific antibodies to some of these antigens, using single clones of lymphocyte-myeloma hybrid cells; and then to label the antibodies with a suitable radionuclide. The potential clinical applications include both localization and treatment of the tumours (Hammersmith Oncology Group, 1984; Begent and Jewkes, 1986; Britton and Granowska, 1988). Carcinoembryonic antigen (CEA) is expressed by colorectal carcinomas and much experience is available of using its antibody labelled with 131Iand 1231.The quality of the images is only moderately good because of the relatively low uptake by the tumour and complicated subtraction techniques have been devised to improve the image quality. The most promising display techniques take account of temporal changes in activity over serial images, so that significant changes that identify tumour sites are given an appropriate colour code on the final image (Granowska et al., 1988). The technique does not supplant conventional methods of detecting primary tumours and is unsuitable for screening because it is not tumour specific and involves the injection of a foreign protein. Indeed a negative intradermal test is an essential prerequisite for continuing the investigation. Its application in staging colorectal carcinoma is limited because pelvic lymph nodes may trap the antigen cells even when there is no tumour. The most promising use is in detecting recurrence after primary surgical treatment. It is well known that fibrous tissue in the pelvis can mimic carcinoma on computed tomography and a radioimmuno scan enables the differentiation. For biophysical reasons 123I is a more satisfactory label than 1311and recently Ill Inanti CEA antibodies have been recommended because of their greater stability and improved pharmacokinetics. Even so, their lack of tumour specificity cause liver metastasis to be overlooked, and false positives to arise from inflammatory bowel disease (Bares et al., 1989). CONCLUSION Radionuclide imaging is an indispensable part of the diagnosis and management of bowel disorders. The tests require little or no preliminary preparation and can be done on out-patients. The investigations described here are not exhaustive and do not include well established radionuclide techniques that are laboratory based and usually outside the scope of diagnostic radiology. The imaging techniques should be available to all radiologists who aspire to higher accuracy and greater effectiveness.
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CLINICAL RADIOLOGY
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