- Email: [email protected]
APPRAISAL OF THE APPLICATION OF 99mTc IN THE ASSESSMENT OF GASTRIC FUNCTION
648 this enzyme. Histochemical studies indicate that conjugated bilirubin is present within liver cells in intrahepatic cholestasis (Raia 1967), and an increase in the amount of conjugated bilirubin in the cells resulting from increased conjugation might then increase the excretion of bilirubin into the bile. The rise in the ratio of plasma-directbilirubin to total bilirubin measurements could be due to a reflux of conjugated pigment into the blood, such as happens in healthy subjects who are given a load of bilirubin and in hxmolysis (Tisdale et al. 1959, Billing et al. 1964a). Direct-bilirubin readings higher than those for total bilirubin have been reported by Baer and Wood (1967), and with other methods. The mechanism of this is being investigated, but measurement of the change in the level of the direct reacting compounds, rather than absolute levels, is valid. An alternative explanation of the action of phenobarbitone is that enzymes in the liver (or in other tissues), which ordinarily metabolise bilirubin less actively than glucuronyl transferase, may be induced to do so by phenobarbitone (Schmid 1967), as might glucuronyl transferase itself in other tissues where it is known to be present (Grodsky and Carbone 1957). There are also pathways of bile-pigment excretion which might be increased in size by phenobarbitone. Thus, a large part of hxm injected into rats is excreted neither in bile nor urine (Ostrow et al. 1962), and in the unconjugated hyperbilirubinasmia of Gunn rats and the Crigler-Najjar syndrome a large part of the bilirubin is excreted as unidentified products across the bowel wall (Schmid and Hammaker 1963, Billing et al. 1964b). In conjugated hyperbilirubinxmia, bilirubin is excreted in the urine Fevery et al. 1967); and, since phenobarbitone may increase the renal clearance of sulphadimethoxine (Remmer and Merker 1965), it is possible that the excretion of bilirubin in the urine is increased in our
helpful advice and discussion; Dr. D. Doniach, who carried out the immunofluorescent tests; and Dr. J. P. H. Davies, Dr. T. H. Howell, Dr. S. B. Karani, and Dr. A. J. Karlish for referring the patients to us. The work was supported by the Medical Research Council. Requests for reprints should be addressed to R. W. REFERENCES
Baer, D. M., Wood, D. C. (1967) Clin. chim. Acta, 17, 1. Barrett, P. V. D., Cline, M. J., Berlin, N. I. (1966) J. clin. Invest. 45, 1657. Billing, B. H., Gray, C. H., Kulczycka, A., Manfield, P., Nicholson, D. C. (1964b) Clin. Sci. 27, 163. Williams, R., Richards, T. G. (1964a) ibid. p. 245. Catz, C., Yaffe, S. J. (1962) Am. J. Dis. Child. 104, 516. Crigler, J. F., Gold, N. I. (1966) J. clin. Invest. 45, 998. Datta, D. V., Sherlock, S., Scheuer, P. J. (1963) Gut, 4, 223. Fevery, J., Heirwegh, K., de Groote, J. (1967) Clin. chim. Acta. 17, 63. Gartner, L. M. (1967) in Bilirubin Metabolism (edited by I. A. D. Bouchier and B. H. Billing). Oxford. Grodsky, G. M., Carbone, J. V. (1957) J. biol. Chem. 226, 449. Israels, L. G., Levitt, M., Novak, W., Foerster, J., Zipursky, A. (1967) in Bilirubin Metabolism (edited by I. A. D. Bouchier and B. H. Billing). —
Oxford.
Metge, W. R., Owen, C. A., Jr., Foulk, W. T., Hossman, H. N. (1964) J. Lab. clin. Med. 64, 335. Michaelis, M. (1961) Scand. J. clin. Lab. Invest. 13, Suppl. 56. Nosslin, B. (1960) ibid. 12, suppl. 49. Ostrow, J. D., Jandl, J. H., Schmid, R. (1962) J. clin. Invest. 41, 1628. Raia, S. (1967) in Bilirubin Metabolism (edited by I. A. D. Bouchier and B. H. Billing). Oxford. Remmer, H. (1962) in Enzymes and Drug Action. Ciba Symposium (edited by J. L. Mongar and A. V. S. de Reuck). London. Merker, H. J. (1965) Ann N.Y. Acad. Sci. 123, 79. Robinson, S. H., Tsong, M., Brown, B. W., Schmid, R. (1966) J. clin. Invest. 45, 1569. Schmid, R. (1967) in Bilirubin Metabolism (edited by I. A. D. Bouchier and B. H. Billing). Oxford. Hammaker, L. (1963) J. clin. Invest. 42, 1720. Sherlock, S. (1959) Gastroenterology, 37, 574. Tisdale, W. A., Klatskin, G., Kinsella, E. D. (1959) Am. J. Med. 26, 214. Whelton, M. T., Krustev, L. P., Billing, B. H. (1967) Unpublished. Yaffe, S. J., Levy, G., Matsuzawa, T., Baliah, T. (1966) New Engl. J. Med. 275, 1461. —
—
APPRAISAL OF THE APPLICATION OF 99mTc IN THE ASSESSMENT OF GASTRIC FUNCTION W. J. IRVINE M.B., B.Sc. Edin.,
patients.
One observation which is difficult to reconcile with our findings is the increase in rats of the excretion of bilirubin in the early labelled peak in bile by phenobarbitone. This peak is the fraction of radioactive labelled bilirubin which is excreted in the first 4-6 days after administration of a labelled precursor, and comes from ineffective erythropoiesis in the marrow, and from the breakdown of hsemcontaining enzymes, mainly cytochromes in the liver (Robinson et al. 1966), and kidney (Israels et al. 1967). Though there is some evidence that the early labelled peak may be different in man (Barrett et al. 1966), it is difficult to see how this effect of phenobarbitone could lower the plasma-bilirubin level. Other possible explanations of our findings would be a reduction of ineffective erythropoesis, or lengthening of the life of the red-blood-cells. Both seem
unlikely.
This action of phenobarbitone may be of considerable value in the treatment of chronic cholestatic jaundice. All four patients noticed a striking decrease in itching and an improvement in wellbeing in addition to the lessened jaundice. Although cholestyramine has proved useful in controlling itching in jaundice, the drug is unpleasant to take and in some patients ineffective. The alternative, norethandrolone, always increases jaundice while relieving itching (Sherlock 1959). Phenobarbitone is unlikely to alter the course of the underlying disease; to date none of the other liver-function tests have changed in our patients, but some symptomatic relief is worth while. Further longterm studies are needed. We thank Prof. C. H.
Gray and Dr.
D. C. Nicholson for much
A. G. STEWART M.B. St. And., M.R.C.P., M.R.C.P.E.
M.R.C.P.E. CONSULTANT PHYSICIAN
NICHOLAS RESEARCH FELLOW
G. P. MCLOUGHLIN B.Sc.
P. TOTHILL B.Sc., Ph.D. F.Inst.P.
PHYSICIST
PRINCIPAL PHYSICIST
From the Endocrine Clinic, M.R.C. Clinical Endocrinology Research Unit, and Departments of Therapeutics, and Medical
Physics, Royal Infirmary, Edinburgh In a study of nineteen subjects the secretion of 99mTc into gastric juice has been shown to correlate closely with the volume of the gastric secretion and to a lesser extent with the acid and with the intrinsic-factor secretion during the posthistamine hour. The isotope is also secreted in the saliva. The mean gastric uptake of the isotope as determined by scanning in the absence of stimulation or aspiration of gastric juice is low in patients with achlorhydria compared with those capable of secreting acid, but the overlap in results for individual patients precludes gastric scanning at one hour as a useful test for gastric function. Alternative procedures are suggested which may lead to 99mTc studies providing a quantitative index of gastric function without intubation and which is suitable for clinical use. Summary
Introduction THE concentration of the metastable isotope 99mTc as pertechnetate in the stomach and its detection by gastric scanning has been reported in animals and in man (Harper et
al. 1962, Andros
et
al. 1965, Herbert
et
al.
1965). The
649
short physical half-life of 6 hours, 140keV gamma emission and absence of beta radiation makes the radionuclide 99mTc an ideal scanning agent. Harden et al. (1967a) reported the gastric uptake of technetium in ten healthy volunteers and two patients. We have evaluated 99mTc in the assessment of gastric function with particular reference to atrophic gastritis in the hope that a satisfactory test of gastric function might be devised without the necessity for intubation. Patients and Methods Patients We investigated nineteen individuals; five had frank
pernicious anxmia diagnosed by the presence of a megaloblastic anaemia and low serum-vitamin-B12, histamine-fast achlorhydria, the presence of antibody to gastric parietal cells, and abnormal absorption of vitamin B12 (Schilling test) corrected by the addition of intrinsic factor. Two had latent pernicious anaemia with the findings described above but no anaemia. The diagnoses in the remaining eleven patients are shown in table I and represent patients with thyroid abnormalities who were studied for evidence of associated atrophic gastritis, patients with iron-deficiency anaemia, peptic ulcer, hypertrophy of the gastric mucosa; one healthy volunteer also participated. Gastric
Analysis
An augmented histamine test of gastric acid secretion was carried out in all subjects. After a 12-hour fast a gastric tube was positioned under fluoroscopic control and the fasting residue was aspirated and discarded. Samples of gastric juice were collected by continuous suction during the ensuing hour. Histamine acid phosphate (0-04 mg. per kg. body-weight) was then injected subcutaneously. 50-100 mg. of mepyramine maleate was given intramuscularly 20-30 minutes before the injection of histamine. Gastric aspiration, supplemented by hand suction and careful positioning of the patient, was continued for 1 hour after the injection of histamine. The post-histamine hour was subdivided into three 20-minute periods and the samples of gastric juice were collected accordingly. The volume of each sample of gastric juice was recorded and the pH was determined by pH meter. Samples were then titrated for acid and intrinsic-factor content. The acid was titrated against 0-1 N sodium hydroxide to pH 7 using automatic titration (Radiometer, Copenhagen). The intrinsicfactor content was determined by immunoassay using the albumin-coated charcoal method (Irvine 1966). TABLE I-ANALYSIS OF GASTRIC
JUICE,
99ffiTc Studies 99ffiTc was obtained
as the pertechnetate by elution with 10 ml. of sterile physiological saline solution from a column generator loaded with molybdenum-99 (Radiochemical Centre, Amersham, England). The eluate was sterilised by autoclaving. A tracer dose of up to 500 fLC [Tc]-pertechnetate was given intravenously at the beginning of the basal collection of gastric juice in an otherwise standard augmented histamine test as described above. 1 ml. aliquots of each sample of gastric aspirate were counted in a well-type scintillation counter. The radioactivity in the gastric juice aspirated during the basal hour, and during the post-histamine hour was expressed as a percentage of the dose administered. Scanning over the stomach area was carried out with a’Type 1700 ’scanner (Nuclear Chicago Corporation) with the patient lying supine. The detecting head was constructed in the Department of Medical Physics, Royal Infirmary, Edinburgh, and contained a 7-5 cm. x 7-5 cm. sodium-iodide crystal. The collimator had 37 holes, focused at 7-5 cm. from the face and was designed primarily for detecting 1311 gamma-radiation. The scanner was operated at its maximum speed of 30 cm. per minute, with a line spacing of 0.6 cm. Under these conditions a stomach scan took 15-20 minutes. The radioactive content of the stomach was assessed from the scan by counting dots in the appropriate area and subtracting the background count-rate determined from a neighbouring area of the scan. Calibration was achieved by scanning a sample of the administered dose made up to a known volume in a polyethylene bottle and placed in a standard position. Comparisons were also made between the scanning response to this standard and that from an equal dose in a stomach phantom at different depths below the surface. The depth chosen to correspond to the most likely position of the stomach in patients was 4 cm. below the anterior surface. The effective depth of the stomach varies from patient to patient, and to the extent that this differs from the model the assessment of stomach uptake will be in error. It is thought that this error is unlikely to exceed 20%. A scan of the stomach was obtained in all patients immediately after completion of the augmented histamine test and in some patients aspiration was continued for a further hour and the scan repeated. Gastric scanning, without aspiration and without histamine, was repeated in twelve patients. In these the stomach area was scanned at 1 hour and/or 2 hours after 99ffiTc (table n). In two patients gastric scanning was done at the end of the basal hour and at the end of the post-histamine hour but without gastric aspiration.
GASTRIC
SEROLOGY,
AND CLINICAL DIAGNOSIS
650 TABLE
II-GASTRIC
UPTAKE
AFTER
..roTe
WITHOUT
HISTAMINE
OR
ASPIRATION
Saliva The
content of 99mTc in the saliva was 15% of the dose per litre at 30 minutes in patient no. 14, 104% at 3 hours in patient no. 1, and 212% at 3 hours in patient no. 2.
Gastric Scanning In twelve of the nineteen subjects the 99mTc uptake of the stomach was measured by scanning at 1 and/or 2 hours without gastric aspiration or gastric stimulation (table 11). The gastric uptake (expressed as % dose) at 1 hour ranged from 2-2 to 9-5 (mean 4-1) in five patients with pernicious anxmia, from 1-8 to 5-0 (mean 3-4) in two patients with achlorhydria, and from 2-8 to 13-3 (mean 6-5) in six patients with greater than 5 mEq. hydrochloric acid secretion in
*
Patients with
pernicious anaernia.
Venous blood-samples were withdrawn at approximately half-hour intervals throughout the procedure, and the radioactivity was counted in whole blood, and in plasma and red-blood-cell fractions. In three patients the radioactivity in samples of saliva was measured at intervals after administration of 99mT and expressed as a percentage of the dose administered per litre of saliva. Gastric Serology The sera of the patients were tested for the presence of gastric parietal-cell antibody by the indirect fluorescentantibody technique (Irvine 1963) and for antibody to intrinsic factor by the albumin-coated charcoal technique (Irvine 1966). Results
Gastric Aspirate in the Post-histamine Hour The results of the analysis of the gastric juice obtained during the post-histamine hour, the gastric serology, and the clinical diagnosis are shown for the individual patients in table I. Fig. 1 shows the correlation between the 99mTc content (% dose) and (a) volume, (b) acid content, and (c) intrinsic-factor content of the post-histamine hour gastric aspirate. The 99mTc content of the gastric aspirate was significantly correlated with each of the other measures of gastric function. The correlation is particularly good with the volume of the gastric juice and there is also a good correlation between the isotope content and the acid content. The correlation between the 99mTc content and the volume of gastric juice in the post-histamine hour is significantly better than the correlation between the 99mTc content and acid output in the same samples (p < 0-001). The regression coefficients (r) for the correlation between 99mTc content and the volume, acid content, and intrinsic-factor content of the post-histamine hour gastric juice are 0-96, 0-91, and 0-75, respectively. In achlorhydric patients the concentration of 99mTc (% dose per litre) was greatest in the gastric aspirate obtained during the second 20-minute period after histamine, while in acid-producing individuals the greatest concentration of the isotope was obtained in the first 20 minutes after histamine. In both achlorhydric and acid-producing individuals the greatest amount of the isotope was obtained in the aspirate during the second 20-minute period after histamine, when the volume of the aspirate was also greatest. In the basal hour, 99mTc in the aspirate and the volume, acid, or intrinsic-factor content of the gastric aspirate were not significantly correlated.
Fig. 1-Correlations between
"mTc content and
measures
of gastric
function.
(a) Correlation between the ’i°Tc content and the (r=0-96) of the gastric aspirate in the post-histamine hour.
volume
(b) Correlation between the ..mTe content and the acid content (r=0-91) of the gastric aspirate in the post-histamine hour. (c) Correlation between the °°mTc content and the intrinsic factor content (r=0-75) of the gastric aspirate in the post-histamine hour.
651
without histamine or aspiration at 1 hour after aemTc in patient with pernicious ana:mia.
Fig. 3-Patient 1 : gastric
Fig. 2-Patient 11: gastric scan at 2 hours without histamine and without aspiration in patient with normal gastric acid secretion. The percentage uptake 99mTc at this time was calculated to be
scan
Fig. 4-Patient 4: gastric scan at 2 hours after histamine (3 hours after "mTc) in patient with pernicious anaemia. Continuous gastric aspiration was done.
the
region, but is more probably due to pooled gastric juice or saliva. There is only a small amount of radioactivity above background level elsewhere in the stomach region. Fig. 4 is a gastric scan at 2 hours after histamine and
1-hour scan between the three groups. Table 11 also shows the reproducibility of 1-hour scans done on the same patients on separate days without aspiration. Fig. 2 shows a gastric scan at 2 hours in patient no. 11 who had a normal gastric acid secretion (7-7 mEq. in the post-histamine hour). The gastric uptake of 99mTc was calculated from this scan as 58%, The fundus, body, and pyloric region of the stomach are all clearly shown. There was no evidence of increased amounts of radioactivity in the duodenum or lower in the small intestine. Fig. 3 shows a gastric scan taken at 1 hour after administration of 99mTc in a patient with pernicious anaemia (no. 1). A small area of increased radioactivity is seen in the region of the fundus of the stomach. This could be due to concentration of the isotope in the mucosa
3 hours after the administration of 99mTc with continuous gastric aspiration in another patient with pernicious ansemia (no. 4). In contrast to the patient shown in fig. 3 the gastric uptake of 99mTc is apparent in all regions of the stomach and the general appearance of the scan is similar to that of the patient in fig. 2 who had a normal gastric acid secretion. This scan establishes that atrophic gastric mucosa may still be capable of taking up 99mTc even although there is achlorhydria and lack of secretion of intrinsic factor. The gastric uptake of 99mTc as determined by scanning without histamine stimulation and without gastric aspiration is greater after 2 hours than it is after 1 hour (table 11). The effect of histamine on gastric uptake as determined by scanning was studied in detail in one patient (no. 15) and the findings are shown in fig. 5. The following three experiments were done:
5-8%.
post-histamine hour. While this indicates a trend of increasing gastric uptake of s9mTc with increasing acid output, there is considerable overlap in the results of the
of that
(a) The gastric uptake was measured by scanning at 1 hour and at 2 hours after the intravenous administration of 99mTc. No histamine was given and no gastric aspiration was done. The uptake at 2 hours (10-2%) was substantially higher than at 1 hour (3-7%). (b) The experiment was repeated, again without gastric aspiration, but histamine was given subcutaneously at 1 hour. The gastric uptake at 2 hours (4-7%) was virtually the same as at 1 hour (4-5%). (c) Gastric aspiration was carried out for 1 hour before histamine and for 1 hour after histamine and the gastric uptake determined by scanning at the end of the post-histamine hour. The 99mTc content of the gastric juice was 5-6% during the basal hour and 11.7% during the post-histamine hour. The gastric uptake determined by scanning at the end of the 2 hours of aspiration (6-2%) was only slightly greater than the result obtained at 1 hour after histamine but without aspiration in experiment (b) (4-7%) and considerably lower than the 2-hour gastric uptake without histamine or aspiration in experiment (a) (10-2%). It may be concluded from this series of experiments that after histamine much of the gastric juice may be lost from the stomach via the duodenum if aspiration is not carried out. The loss of radioactive gastric juice from the stomach after histamine stimulation can also be demonstrated directly by gastric scanning as shown in fig. 6 (patient
18). Fig. 7 illustrates that the distribution of radioactivity in a gastric scan can be influenced by the pooling of gastric juice in the fundus of the stomach.
no.
Fig. 5-Patient 15:
’9mTc studies showing the effect of histamine secretiora with loss of the isotope from the stomach.
on
652 the intrinsic-factor content of the gastric juice. The correlation between volume and acid secretion is such that a test of gastric function based on volume secretion after or
augmented histamine stimulation would have definite potential. However, there are difficulties in the
of 99mTc to the clinical Unless continuous aspiration is done, an unknown amount of the gastric juice may be lost from the stomach via the duodenum, and swallowed saliva may add significantly to the radioactivity recorded over the stomach area or in the gastric aspirate. If it is accepted that gastric aspiration is required, it is clear that 99mTc scans will provide no more information than simply recording the volume of the aspirate. The gastric uptake of 99mTc by the stomach without histamine stimulation is such that in patients who are normal acid producers the stomach is clearly shown by direct
application
assessment of gastric function.
Fig. 6-Patient 18: gastric scans. ’9m’Tc uptake. (b) 1 hour later and after histamine to show the loss of "’mTc into the small intestine. No gastric aspiration.
(a) 1-hour
Fig. 7-Patient 15: effect of aspiration
on
the "fundal pool".
(a) Gastric scan 1/s hours after histamine and 30 minutes after aspiration had stopped (gastric uptake = 6-3 %). (b) Gastric scan after a further half-hour and immediately following aspiration of 62 ml. gastric juice containing 5-5 mEq. hydrochloric acid and 4-3% of the dose of "mTc (gastric uptake 2-8%). Block by Perchlorate In one patient the gastric uptake of 99mTc was found to be completely blocked by the previous ingestion of 200 mg. perchlorate by mouth. Blood-levels 99mTc The measurements of blood radioactivity showed that blood concentrations of 99mTc fell during the period of aspiration of gastric juice in a roughly exponential manner, the curve corresponding to an average half-time of 2-7 hours. Discussion After the intravenous administration of 99mTc to the mouse, 25% of the dose can be demonstrated in the stomach plus contents removed 30 minutes later, and about 1% localises in the thyroid (Harper et al. 1962). Localisation is inhibited by perchlorate or iodide and 99mTc that has already been taken up can be discharged by these agents. Pertechnetate, the most easily available form of the isotope, is distributed in the body in the same way as inorganic iodide. After intravenous administration in man, the isotope is concentrated in the salivary glands, thyroid, stomach, and urinary bladder (Tothill and Irvine 1967). 99mTc, with its ideal scanning characteristics and short half-life, has been used effectively in thyroid scanning (Andros et al. 1965, Degrossi et al. 1965, Tothill and Irvine 1967). Various compounds of 99mTc have also been used successfully for scanning of the brain, salivary glands, liver, spleen, kidney, and placenta, and in inhalation scanning and cisternography (Harper et al. 1966, Harden et al. 1967b). The secretion of intravenously administered 99mTc into the gastric juice after histamine correlates more closely with the volume of the gastric secretion than with the acid
scanning. however, the stomach of some patients with pernicious anxmia may be almost as clearly visualised by the same procedure.
The abilitv of the stomach to acid in response to histamine tends to be correlated with the uptake of the isotope by the stomach at 1 or 2 hours without histamine stimulation and without gastric aspiration, but not sufficiently closely for the 99mTc-uptake measurement to be a useful assessment of gastric function. It might be expected that the concentration of 99mTc in gastric juice would be related to the concentration in plasma at the time of secretion. However, during the basal hour the collection of juice was not divided so no information about this was obtained. The effect of injection of histamine on pertechnetate levels in gastric contents masked any changes due to falling plasma concentration. In the measurement of the gastric uptake of 99mTc by scanning without aspiration, the difficulties of loss of gastric juice from the stomach area and the addition to the stomach of radioactive saliva may be partly overcome by an injection of atropine or other agent that will reduce gastric motility and the secretion of saliva. The use of an early gastric uptake of 99mTc 10-15 minutes after gastric stimulation with histamine or pentagastrin and using a rapid and sensitive scanner also requires further study. It is doubtful whether gastric scanning will provide information on gastric position or mucosal lesions that is not better obtained by a standard radiographic technique with contrast media. As suggested by Harper et al. (1962), a possible exception may be ectopic gastric mucosa in a Meckel’s diverticulum. One of the limiting factors in the demonstration of mucosal lesions in the stomach is that, if tubal aspiration is to be avoided, radioactive gastric juice and saliva may pool in the fundus of the stomach or in the region of the pylorus. Also, the resolution obtainable by scanning is limited by the physical characteristics of the instrument used and the fact that the radioactivity from both layers of the mucosa is superimposed. secrete
653 We are grateful to Dr. Howard Davies, of the department of heematology, for his cooperation and to Mr. Kenneth Marwick and
Miss Laura Scarth for their invaluable technical assistance. Requests for reprints should be addressed to W. J. 1., M.R.C. Clinical Endocrinology Research Unit, 2, Forrest Road, Edinburgh.
V., Lathrop,
K.
A., McCardle,
R.
J. (1965) J. clin.
Degrossi, O., Gotta, H., Olivari, A., Pecorini, V., Chwojnik, A. (1965) Nucl. Med. 4, 383. Harden, R. McG., Alexander, W. D., Kennedy, I. (1967a) Lancet, i, 1305. Hilditch, T. E., Kennedy, I., Mason, D. K., Papadopoulos,, S. Alexander, W. D. (1967b) Clin. Sci. 32, 49. Harper, P. V., Andros, G., Lathrop, K. (1962) Semi-a. Rep. Argonne Cancer Res. Hosp. 18, 76. Lathrop, K. A., Gottschalk, A. (1966) Proc. Symp. Oak Ridge Instit. —
—
Nucl. Stud. Nov. 1965; Radioact. Pharmac., U.S. Atomic Energy
Commission, chpt. 18, 335. Herbert, R., Kulke, W., Shepherd, R. T. H. (1965) Postgrad. med. J. 41, 656. Irvine, W. J. (1963) Q. Jl exp. Physiol. 48, 427. (1966) Clin. exp. Immun. 1, 99. Tothill, P., Irvine, W. J. (1967) Int. Symp. radioact. Isotopes clin. Med. Res. Bad Gastein, 1967. 10, 29. —
ORAL CONTRACEPTIVES AND HYPERTENSION
JAMES W. WOODS M.D. Vanderbilt PROFESSOR OF MEDICINE, UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE, CHAPEL HILL
Summary
Six patients in whom hypertension may have been intensified by oral contraceptives
described.
are
THE suspicion that hypertension may be aggravated by oral contraceptives has existed among some of the staff of our institution for three years. It has recently become apparent from conversations that this suspicion is shared by others. To our knowledge, such an association has not been reported. The purpose of this communication is to present the cases which serve as a basis for our suspicion, and thereby to encourage examination of the possibility that oral contraceptives may intensify pre-existing hypertension and may perhaps precipitate hypertension in certain patients. These cases have come to our attention without a special search.
Case-reports Case1 A 28-year-old woman was normotensive during and after each of two pregnancies 5 and 3 years ago. After the second pregnancy she was placed on ’Orthonovum’ by
her personal physician and
was not
examined
again until March, 1967, when she
was seen
North Carolina Memorial
Hospital because frequent headaches; her blood-pressure was found to be 180/110 mm. Hg on repeated determinations. She said that a 17 Ib. weight gain had followed exhibition of the oral contraceptive and that she had " not felt well of
There was no family history of and no past history of renal disease. Physical examination was negative except for the raised blood-pressure, and laboratory studies directed toward discovery of a specific cause for the hypertension were negative. Orthonovum was discontinued and her subsequent course is shown in the
since",
hypertension
weeks, 136/90
blood-pressure
was
114/75 after
at
110/70.
Case 2 A 27-year-old woman had been found to have a bloodpressure of 120/74 mm. Hg in August, 1961, of 126/80 in August, 1962, of 120/70 in November, 1963, and normal values in 1964 throughout her lst pregnancy. After delivery in September, she was started on’Ovulin B (Edema of the ankles and a 10 lb. weight gain promptly ensued. 6 weeks later, her blood-pressure was 150/95, and 7 weeks later 155/105. Ovulin was discontinued, and in February, 1965, her body-weight had returned to normal and her blood-pressure was 130/80. When she was last seen in March, 1965, her blood-pressure was
128/82. Case 3 A 27-year-old woman developed acute glomerulonephritis in 1960, during her only pregnancy. Her blood-pressure during this illness and on regular, frequent visits to her physician up to January, 1965, was at the upper limits of the normal range but never over 140/90 mm. Hg. In January, 1965,’Enovid-E ’ was started. Her body-weight and girth rapidly increased, and
pretibial
cedema
appeared;
her
blood-pressure
was
180/120.
She was admitted to the North Carolina Memorial Hospital where an intravenous pyelogram was normal and creatinine clearance was 98 ml. per minute, but percutaneous renal biopsy revealed mild glomerulonephritis. After discontinuance of enovid-E and administration of a thiazide diuretic, the oedema disappeared, weight returned to normal, and hypertension abated. On subsequent visits to her physician up to January, 1967, her blood-pressure levels fluctuated between 130/90 and
150/100. Introduction
at
The
10 weeks, and 132/80 at 121/2 weeks. Orthonovum was then restarted. The patient gained 3 lb. in weight, and 4 weeks later her blood-pressure was 160/100. The drug was discontinued, and 9 weeks later the blood-pressure 6
was
REFERENCES
Andros, G., Harper, P. Endocr. 25, 1067.
accompanying figure.
Case 4 A
42-year-old woman had had 5 uneventful pregnancies. In hypertension, proteinuria, or oedema present. Her mother was known to have hypertension, and both parents had
none was
suffered strokes. In 1963 she was started on orthonovum. In August, 1965, she was referred to North Carolina Memorial Hospital for evaluation of recently discovered hypertension with blood-pressure consistently around 200/110 mm. Hg. Investigations revealed no cause for her hypertension. Orthonovum was discontinued, and a mild antihypertensive agent (’ Ser-Ap-Es’) was prescribed. The blood-pressure Case 1: systolic (x) and diastolic (o) bloodpressure related to intake of oral contraceptive.
helpful advice and discussion; Dr. D. Doniach, who carried out the immunofluorescent tests; and Dr. J. P. H. Davies, Dr. T. H. Howell, Dr. S. B. Karani, and Dr. A. J. Karlish for referring the patients to us. The work was supported by the Medical Research Council. Requests for reprints should be addressed to R. W. REFERENCES
Baer, D. M., Wood, D. C. (1967) Clin. chim. Acta, 17, 1. Barrett, P. V. D., Cline, M. J., Berlin, N. I. (1966) J. clin. Invest. 45, 1657. Billing, B. H., Gray, C. H., Kulczycka, A., Manfield, P., Nicholson, D. C. (1964b) Clin. Sci. 27, 163. Williams, R., Richards, T. G. (1964a) ibid. p. 245. Catz, C., Yaffe, S. J. (1962) Am. J. Dis. Child. 104, 516. Crigler, J. F., Gold, N. I. (1966) J. clin. Invest. 45, 998. Datta, D. V., Sherlock, S., Scheuer, P. J. (1963) Gut, 4, 223. Fevery, J., Heirwegh, K., de Groote, J. (1967) Clin. chim. Acta. 17, 63. Gartner, L. M. (1967) in Bilirubin Metabolism (edited by I. A. D. Bouchier and B. H. Billing). Oxford. Grodsky, G. M., Carbone, J. V. (1957) J. biol. Chem. 226, 449. Israels, L. G., Levitt, M., Novak, W., Foerster, J., Zipursky, A. (1967) in Bilirubin Metabolism (edited by I. A. D. Bouchier and B. H. Billing). —
Oxford.
Metge, W. R., Owen, C. A., Jr., Foulk, W. T., Hossman, H. N. (1964) J. Lab. clin. Med. 64, 335. Michaelis, M. (1961) Scand. J. clin. Lab. Invest. 13, Suppl. 56. Nosslin, B. (1960) ibid. 12, suppl. 49. Ostrow, J. D., Jandl, J. H., Schmid, R. (1962) J. clin. Invest. 41, 1628. Raia, S. (1967) in Bilirubin Metabolism (edited by I. A. D. Bouchier and B. H. Billing). Oxford. Remmer, H. (1962) in Enzymes and Drug Action. Ciba Symposium (edited by J. L. Mongar and A. V. S. de Reuck). London. Merker, H. J. (1965) Ann N.Y. Acad. Sci. 123, 79. Robinson, S. H., Tsong, M., Brown, B. W., Schmid, R. (1966) J. clin. Invest. 45, 1569. Schmid, R. (1967) in Bilirubin Metabolism (edited by I. A. D. Bouchier and B. H. Billing). Oxford. Hammaker, L. (1963) J. clin. Invest. 42, 1720. Sherlock, S. (1959) Gastroenterology, 37, 574. Tisdale, W. A., Klatskin, G., Kinsella, E. D. (1959) Am. J. Med. 26, 214. Whelton, M. T., Krustev, L. P., Billing, B. H. (1967) Unpublished. Yaffe, S. J., Levy, G., Matsuzawa, T., Baliah, T. (1966) New Engl. J. Med. 275, 1461. —
—
APPRAISAL OF THE APPLICATION OF 99mTc IN THE ASSESSMENT OF GASTRIC FUNCTION W. J. IRVINE M.B., B.Sc. Edin.,
patients.
One observation which is difficult to reconcile with our findings is the increase in rats of the excretion of bilirubin in the early labelled peak in bile by phenobarbitone. This peak is the fraction of radioactive labelled bilirubin which is excreted in the first 4-6 days after administration of a labelled precursor, and comes from ineffective erythropoiesis in the marrow, and from the breakdown of hsemcontaining enzymes, mainly cytochromes in the liver (Robinson et al. 1966), and kidney (Israels et al. 1967). Though there is some evidence that the early labelled peak may be different in man (Barrett et al. 1966), it is difficult to see how this effect of phenobarbitone could lower the plasma-bilirubin level. Other possible explanations of our findings would be a reduction of ineffective erythropoesis, or lengthening of the life of the red-blood-cells. Both seem
unlikely.
This action of phenobarbitone may be of considerable value in the treatment of chronic cholestatic jaundice. All four patients noticed a striking decrease in itching and an improvement in wellbeing in addition to the lessened jaundice. Although cholestyramine has proved useful in controlling itching in jaundice, the drug is unpleasant to take and in some patients ineffective. The alternative, norethandrolone, always increases jaundice while relieving itching (Sherlock 1959). Phenobarbitone is unlikely to alter the course of the underlying disease; to date none of the other liver-function tests have changed in our patients, but some symptomatic relief is worth while. Further longterm studies are needed. We thank Prof. C. H.
Gray and Dr.
D. C. Nicholson for much
A. G. STEWART M.B. St. And., M.R.C.P., M.R.C.P.E.
M.R.C.P.E. CONSULTANT PHYSICIAN
NICHOLAS RESEARCH FELLOW
G. P. MCLOUGHLIN B.Sc.
P. TOTHILL B.Sc., Ph.D. F.Inst.P.
PHYSICIST
PRINCIPAL PHYSICIST
From the Endocrine Clinic, M.R.C. Clinical Endocrinology Research Unit, and Departments of Therapeutics, and Medical
Physics, Royal Infirmary, Edinburgh In a study of nineteen subjects the secretion of 99mTc into gastric juice has been shown to correlate closely with the volume of the gastric secretion and to a lesser extent with the acid and with the intrinsic-factor secretion during the posthistamine hour. The isotope is also secreted in the saliva. The mean gastric uptake of the isotope as determined by scanning in the absence of stimulation or aspiration of gastric juice is low in patients with achlorhydria compared with those capable of secreting acid, but the overlap in results for individual patients precludes gastric scanning at one hour as a useful test for gastric function. Alternative procedures are suggested which may lead to 99mTc studies providing a quantitative index of gastric function without intubation and which is suitable for clinical use. Summary
Introduction THE concentration of the metastable isotope 99mTc as pertechnetate in the stomach and its detection by gastric scanning has been reported in animals and in man (Harper et
al. 1962, Andros
et
al. 1965, Herbert
et
al.
1965). The
649
short physical half-life of 6 hours, 140keV gamma emission and absence of beta radiation makes the radionuclide 99mTc an ideal scanning agent. Harden et al. (1967a) reported the gastric uptake of technetium in ten healthy volunteers and two patients. We have evaluated 99mTc in the assessment of gastric function with particular reference to atrophic gastritis in the hope that a satisfactory test of gastric function might be devised without the necessity for intubation. Patients and Methods Patients We investigated nineteen individuals; five had frank
pernicious anxmia diagnosed by the presence of a megaloblastic anaemia and low serum-vitamin-B12, histamine-fast achlorhydria, the presence of antibody to gastric parietal cells, and abnormal absorption of vitamin B12 (Schilling test) corrected by the addition of intrinsic factor. Two had latent pernicious anaemia with the findings described above but no anaemia. The diagnoses in the remaining eleven patients are shown in table I and represent patients with thyroid abnormalities who were studied for evidence of associated atrophic gastritis, patients with iron-deficiency anaemia, peptic ulcer, hypertrophy of the gastric mucosa; one healthy volunteer also participated. Gastric
Analysis
An augmented histamine test of gastric acid secretion was carried out in all subjects. After a 12-hour fast a gastric tube was positioned under fluoroscopic control and the fasting residue was aspirated and discarded. Samples of gastric juice were collected by continuous suction during the ensuing hour. Histamine acid phosphate (0-04 mg. per kg. body-weight) was then injected subcutaneously. 50-100 mg. of mepyramine maleate was given intramuscularly 20-30 minutes before the injection of histamine. Gastric aspiration, supplemented by hand suction and careful positioning of the patient, was continued for 1 hour after the injection of histamine. The post-histamine hour was subdivided into three 20-minute periods and the samples of gastric juice were collected accordingly. The volume of each sample of gastric juice was recorded and the pH was determined by pH meter. Samples were then titrated for acid and intrinsic-factor content. The acid was titrated against 0-1 N sodium hydroxide to pH 7 using automatic titration (Radiometer, Copenhagen). The intrinsicfactor content was determined by immunoassay using the albumin-coated charcoal method (Irvine 1966). TABLE I-ANALYSIS OF GASTRIC
JUICE,
99ffiTc Studies 99ffiTc was obtained
as the pertechnetate by elution with 10 ml. of sterile physiological saline solution from a column generator loaded with molybdenum-99 (Radiochemical Centre, Amersham, England). The eluate was sterilised by autoclaving. A tracer dose of up to 500 fLC [Tc]-pertechnetate was given intravenously at the beginning of the basal collection of gastric juice in an otherwise standard augmented histamine test as described above. 1 ml. aliquots of each sample of gastric aspirate were counted in a well-type scintillation counter. The radioactivity in the gastric juice aspirated during the basal hour, and during the post-histamine hour was expressed as a percentage of the dose administered. Scanning over the stomach area was carried out with a’Type 1700 ’scanner (Nuclear Chicago Corporation) with the patient lying supine. The detecting head was constructed in the Department of Medical Physics, Royal Infirmary, Edinburgh, and contained a 7-5 cm. x 7-5 cm. sodium-iodide crystal. The collimator had 37 holes, focused at 7-5 cm. from the face and was designed primarily for detecting 1311 gamma-radiation. The scanner was operated at its maximum speed of 30 cm. per minute, with a line spacing of 0.6 cm. Under these conditions a stomach scan took 15-20 minutes. The radioactive content of the stomach was assessed from the scan by counting dots in the appropriate area and subtracting the background count-rate determined from a neighbouring area of the scan. Calibration was achieved by scanning a sample of the administered dose made up to a known volume in a polyethylene bottle and placed in a standard position. Comparisons were also made between the scanning response to this standard and that from an equal dose in a stomach phantom at different depths below the surface. The depth chosen to correspond to the most likely position of the stomach in patients was 4 cm. below the anterior surface. The effective depth of the stomach varies from patient to patient, and to the extent that this differs from the model the assessment of stomach uptake will be in error. It is thought that this error is unlikely to exceed 20%. A scan of the stomach was obtained in all patients immediately after completion of the augmented histamine test and in some patients aspiration was continued for a further hour and the scan repeated. Gastric scanning, without aspiration and without histamine, was repeated in twelve patients. In these the stomach area was scanned at 1 hour and/or 2 hours after 99ffiTc (table n). In two patients gastric scanning was done at the end of the basal hour and at the end of the post-histamine hour but without gastric aspiration.
GASTRIC
SEROLOGY,
AND CLINICAL DIAGNOSIS
650 TABLE
II-GASTRIC
UPTAKE
AFTER
..roTe
WITHOUT
HISTAMINE
OR
ASPIRATION
Saliva The
content of 99mTc in the saliva was 15% of the dose per litre at 30 minutes in patient no. 14, 104% at 3 hours in patient no. 1, and 212% at 3 hours in patient no. 2.
Gastric Scanning In twelve of the nineteen subjects the 99mTc uptake of the stomach was measured by scanning at 1 and/or 2 hours without gastric aspiration or gastric stimulation (table 11). The gastric uptake (expressed as % dose) at 1 hour ranged from 2-2 to 9-5 (mean 4-1) in five patients with pernicious anxmia, from 1-8 to 5-0 (mean 3-4) in two patients with achlorhydria, and from 2-8 to 13-3 (mean 6-5) in six patients with greater than 5 mEq. hydrochloric acid secretion in
*
Patients with
pernicious anaernia.
Venous blood-samples were withdrawn at approximately half-hour intervals throughout the procedure, and the radioactivity was counted in whole blood, and in plasma and red-blood-cell fractions. In three patients the radioactivity in samples of saliva was measured at intervals after administration of 99mT and expressed as a percentage of the dose administered per litre of saliva. Gastric Serology The sera of the patients were tested for the presence of gastric parietal-cell antibody by the indirect fluorescentantibody technique (Irvine 1963) and for antibody to intrinsic factor by the albumin-coated charcoal technique (Irvine 1966). Results
Gastric Aspirate in the Post-histamine Hour The results of the analysis of the gastric juice obtained during the post-histamine hour, the gastric serology, and the clinical diagnosis are shown for the individual patients in table I. Fig. 1 shows the correlation between the 99mTc content (% dose) and (a) volume, (b) acid content, and (c) intrinsic-factor content of the post-histamine hour gastric aspirate. The 99mTc content of the gastric aspirate was significantly correlated with each of the other measures of gastric function. The correlation is particularly good with the volume of the gastric juice and there is also a good correlation between the isotope content and the acid content. The correlation between the 99mTc content and the volume of gastric juice in the post-histamine hour is significantly better than the correlation between the 99mTc content and acid output in the same samples (p < 0-001). The regression coefficients (r) for the correlation between 99mTc content and the volume, acid content, and intrinsic-factor content of the post-histamine hour gastric juice are 0-96, 0-91, and 0-75, respectively. In achlorhydric patients the concentration of 99mTc (% dose per litre) was greatest in the gastric aspirate obtained during the second 20-minute period after histamine, while in acid-producing individuals the greatest concentration of the isotope was obtained in the first 20 minutes after histamine. In both achlorhydric and acid-producing individuals the greatest amount of the isotope was obtained in the aspirate during the second 20-minute period after histamine, when the volume of the aspirate was also greatest. In the basal hour, 99mTc in the aspirate and the volume, acid, or intrinsic-factor content of the gastric aspirate were not significantly correlated.
Fig. 1-Correlations between
"mTc content and
measures
of gastric
function.
(a) Correlation between the ’i°Tc content and the (r=0-96) of the gastric aspirate in the post-histamine hour.
volume
(b) Correlation between the ..mTe content and the acid content (r=0-91) of the gastric aspirate in the post-histamine hour. (c) Correlation between the °°mTc content and the intrinsic factor content (r=0-75) of the gastric aspirate in the post-histamine hour.
651
without histamine or aspiration at 1 hour after aemTc in patient with pernicious ana:mia.
Fig. 3-Patient 1 : gastric
Fig. 2-Patient 11: gastric scan at 2 hours without histamine and without aspiration in patient with normal gastric acid secretion. The percentage uptake 99mTc at this time was calculated to be
scan
Fig. 4-Patient 4: gastric scan at 2 hours after histamine (3 hours after "mTc) in patient with pernicious anaemia. Continuous gastric aspiration was done.
the
region, but is more probably due to pooled gastric juice or saliva. There is only a small amount of radioactivity above background level elsewhere in the stomach region. Fig. 4 is a gastric scan at 2 hours after histamine and
1-hour scan between the three groups. Table 11 also shows the reproducibility of 1-hour scans done on the same patients on separate days without aspiration. Fig. 2 shows a gastric scan at 2 hours in patient no. 11 who had a normal gastric acid secretion (7-7 mEq. in the post-histamine hour). The gastric uptake of 99mTc was calculated from this scan as 58%, The fundus, body, and pyloric region of the stomach are all clearly shown. There was no evidence of increased amounts of radioactivity in the duodenum or lower in the small intestine. Fig. 3 shows a gastric scan taken at 1 hour after administration of 99mTc in a patient with pernicious anaemia (no. 1). A small area of increased radioactivity is seen in the region of the fundus of the stomach. This could be due to concentration of the isotope in the mucosa
3 hours after the administration of 99mTc with continuous gastric aspiration in another patient with pernicious ansemia (no. 4). In contrast to the patient shown in fig. 3 the gastric uptake of 99mTc is apparent in all regions of the stomach and the general appearance of the scan is similar to that of the patient in fig. 2 who had a normal gastric acid secretion. This scan establishes that atrophic gastric mucosa may still be capable of taking up 99mTc even although there is achlorhydria and lack of secretion of intrinsic factor. The gastric uptake of 99mTc as determined by scanning without histamine stimulation and without gastric aspiration is greater after 2 hours than it is after 1 hour (table 11). The effect of histamine on gastric uptake as determined by scanning was studied in detail in one patient (no. 15) and the findings are shown in fig. 5. The following three experiments were done:
5-8%.
post-histamine hour. While this indicates a trend of increasing gastric uptake of s9mTc with increasing acid output, there is considerable overlap in the results of the
of that
(a) The gastric uptake was measured by scanning at 1 hour and at 2 hours after the intravenous administration of 99mTc. No histamine was given and no gastric aspiration was done. The uptake at 2 hours (10-2%) was substantially higher than at 1 hour (3-7%). (b) The experiment was repeated, again without gastric aspiration, but histamine was given subcutaneously at 1 hour. The gastric uptake at 2 hours (4-7%) was virtually the same as at 1 hour (4-5%). (c) Gastric aspiration was carried out for 1 hour before histamine and for 1 hour after histamine and the gastric uptake determined by scanning at the end of the post-histamine hour. The 99mTc content of the gastric juice was 5-6% during the basal hour and 11.7% during the post-histamine hour. The gastric uptake determined by scanning at the end of the 2 hours of aspiration (6-2%) was only slightly greater than the result obtained at 1 hour after histamine but without aspiration in experiment (b) (4-7%) and considerably lower than the 2-hour gastric uptake without histamine or aspiration in experiment (a) (10-2%). It may be concluded from this series of experiments that after histamine much of the gastric juice may be lost from the stomach via the duodenum if aspiration is not carried out. The loss of radioactive gastric juice from the stomach after histamine stimulation can also be demonstrated directly by gastric scanning as shown in fig. 6 (patient
18). Fig. 7 illustrates that the distribution of radioactivity in a gastric scan can be influenced by the pooling of gastric juice in the fundus of the stomach.
no.
Fig. 5-Patient 15:
’9mTc studies showing the effect of histamine secretiora with loss of the isotope from the stomach.
on
652 the intrinsic-factor content of the gastric juice. The correlation between volume and acid secretion is such that a test of gastric function based on volume secretion after or
augmented histamine stimulation would have definite potential. However, there are difficulties in the
of 99mTc to the clinical Unless continuous aspiration is done, an unknown amount of the gastric juice may be lost from the stomach via the duodenum, and swallowed saliva may add significantly to the radioactivity recorded over the stomach area or in the gastric aspirate. If it is accepted that gastric aspiration is required, it is clear that 99mTc scans will provide no more information than simply recording the volume of the aspirate. The gastric uptake of 99mTc by the stomach without histamine stimulation is such that in patients who are normal acid producers the stomach is clearly shown by direct
application
assessment of gastric function.
Fig. 6-Patient 18: gastric scans. ’9m’Tc uptake. (b) 1 hour later and after histamine to show the loss of "’mTc into the small intestine. No gastric aspiration.
(a) 1-hour
Fig. 7-Patient 15: effect of aspiration
on
the "fundal pool".
(a) Gastric scan 1/s hours after histamine and 30 minutes after aspiration had stopped (gastric uptake = 6-3 %). (b) Gastric scan after a further half-hour and immediately following aspiration of 62 ml. gastric juice containing 5-5 mEq. hydrochloric acid and 4-3% of the dose of "mTc (gastric uptake 2-8%). Block by Perchlorate In one patient the gastric uptake of 99mTc was found to be completely blocked by the previous ingestion of 200 mg. perchlorate by mouth. Blood-levels 99mTc The measurements of blood radioactivity showed that blood concentrations of 99mTc fell during the period of aspiration of gastric juice in a roughly exponential manner, the curve corresponding to an average half-time of 2-7 hours. Discussion After the intravenous administration of 99mTc to the mouse, 25% of the dose can be demonstrated in the stomach plus contents removed 30 minutes later, and about 1% localises in the thyroid (Harper et al. 1962). Localisation is inhibited by perchlorate or iodide and 99mTc that has already been taken up can be discharged by these agents. Pertechnetate, the most easily available form of the isotope, is distributed in the body in the same way as inorganic iodide. After intravenous administration in man, the isotope is concentrated in the salivary glands, thyroid, stomach, and urinary bladder (Tothill and Irvine 1967). 99mTc, with its ideal scanning characteristics and short half-life, has been used effectively in thyroid scanning (Andros et al. 1965, Degrossi et al. 1965, Tothill and Irvine 1967). Various compounds of 99mTc have also been used successfully for scanning of the brain, salivary glands, liver, spleen, kidney, and placenta, and in inhalation scanning and cisternography (Harper et al. 1966, Harden et al. 1967b). The secretion of intravenously administered 99mTc into the gastric juice after histamine correlates more closely with the volume of the gastric secretion than with the acid
scanning. however, the stomach of some patients with pernicious anxmia may be almost as clearly visualised by the same procedure.
The abilitv of the stomach to acid in response to histamine tends to be correlated with the uptake of the isotope by the stomach at 1 or 2 hours without histamine stimulation and without gastric aspiration, but not sufficiently closely for the 99mTc-uptake measurement to be a useful assessment of gastric function. It might be expected that the concentration of 99mTc in gastric juice would be related to the concentration in plasma at the time of secretion. However, during the basal hour the collection of juice was not divided so no information about this was obtained. The effect of injection of histamine on pertechnetate levels in gastric contents masked any changes due to falling plasma concentration. In the measurement of the gastric uptake of 99mTc by scanning without aspiration, the difficulties of loss of gastric juice from the stomach area and the addition to the stomach of radioactive saliva may be partly overcome by an injection of atropine or other agent that will reduce gastric motility and the secretion of saliva. The use of an early gastric uptake of 99mTc 10-15 minutes after gastric stimulation with histamine or pentagastrin and using a rapid and sensitive scanner also requires further study. It is doubtful whether gastric scanning will provide information on gastric position or mucosal lesions that is not better obtained by a standard radiographic technique with contrast media. As suggested by Harper et al. (1962), a possible exception may be ectopic gastric mucosa in a Meckel’s diverticulum. One of the limiting factors in the demonstration of mucosal lesions in the stomach is that, if tubal aspiration is to be avoided, radioactive gastric juice and saliva may pool in the fundus of the stomach or in the region of the pylorus. Also, the resolution obtainable by scanning is limited by the physical characteristics of the instrument used and the fact that the radioactivity from both layers of the mucosa is superimposed. secrete
653 We are grateful to Dr. Howard Davies, of the department of heematology, for his cooperation and to Mr. Kenneth Marwick and
Miss Laura Scarth for their invaluable technical assistance. Requests for reprints should be addressed to W. J. 1., M.R.C. Clinical Endocrinology Research Unit, 2, Forrest Road, Edinburgh.
V., Lathrop,
K.
A., McCardle,
R.
J. (1965) J. clin.
Degrossi, O., Gotta, H., Olivari, A., Pecorini, V., Chwojnik, A. (1965) Nucl. Med. 4, 383. Harden, R. McG., Alexander, W. D., Kennedy, I. (1967a) Lancet, i, 1305. Hilditch, T. E., Kennedy, I., Mason, D. K., Papadopoulos,, S. Alexander, W. D. (1967b) Clin. Sci. 32, 49. Harper, P. V., Andros, G., Lathrop, K. (1962) Semi-a. Rep. Argonne Cancer Res. Hosp. 18, 76. Lathrop, K. A., Gottschalk, A. (1966) Proc. Symp. Oak Ridge Instit. —
—
Nucl. Stud. Nov. 1965; Radioact. Pharmac., U.S. Atomic Energy
Commission, chpt. 18, 335. Herbert, R., Kulke, W., Shepherd, R. T. H. (1965) Postgrad. med. J. 41, 656. Irvine, W. J. (1963) Q. Jl exp. Physiol. 48, 427. (1966) Clin. exp. Immun. 1, 99. Tothill, P., Irvine, W. J. (1967) Int. Symp. radioact. Isotopes clin. Med. Res. Bad Gastein, 1967. 10, 29. —
ORAL CONTRACEPTIVES AND HYPERTENSION
JAMES W. WOODS M.D. Vanderbilt PROFESSOR OF MEDICINE, UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE, CHAPEL HILL
Summary
Six patients in whom hypertension may have been intensified by oral contraceptives
described.
are
THE suspicion that hypertension may be aggravated by oral contraceptives has existed among some of the staff of our institution for three years. It has recently become apparent from conversations that this suspicion is shared by others. To our knowledge, such an association has not been reported. The purpose of this communication is to present the cases which serve as a basis for our suspicion, and thereby to encourage examination of the possibility that oral contraceptives may intensify pre-existing hypertension and may perhaps precipitate hypertension in certain patients. These cases have come to our attention without a special search.
Case-reports Case1 A 28-year-old woman was normotensive during and after each of two pregnancies 5 and 3 years ago. After the second pregnancy she was placed on ’Orthonovum’ by
her personal physician and
was not
examined
again until March, 1967, when she
was seen
North Carolina Memorial
Hospital because frequent headaches; her blood-pressure was found to be 180/110 mm. Hg on repeated determinations. She said that a 17 Ib. weight gain had followed exhibition of the oral contraceptive and that she had " not felt well of
There was no family history of and no past history of renal disease. Physical examination was negative except for the raised blood-pressure, and laboratory studies directed toward discovery of a specific cause for the hypertension were negative. Orthonovum was discontinued and her subsequent course is shown in the
since",
hypertension
weeks, 136/90
blood-pressure
was
114/75 after
at
110/70.
Case 2 A 27-year-old woman had been found to have a bloodpressure of 120/74 mm. Hg in August, 1961, of 126/80 in August, 1962, of 120/70 in November, 1963, and normal values in 1964 throughout her lst pregnancy. After delivery in September, she was started on’Ovulin B (Edema of the ankles and a 10 lb. weight gain promptly ensued. 6 weeks later, her blood-pressure was 150/95, and 7 weeks later 155/105. Ovulin was discontinued, and in February, 1965, her body-weight had returned to normal and her blood-pressure was 130/80. When she was last seen in March, 1965, her blood-pressure was
128/82. Case 3 A 27-year-old woman developed acute glomerulonephritis in 1960, during her only pregnancy. Her blood-pressure during this illness and on regular, frequent visits to her physician up to January, 1965, was at the upper limits of the normal range but never over 140/90 mm. Hg. In January, 1965,’Enovid-E ’ was started. Her body-weight and girth rapidly increased, and
pretibial
cedema
appeared;
her
blood-pressure
was
180/120.
She was admitted to the North Carolina Memorial Hospital where an intravenous pyelogram was normal and creatinine clearance was 98 ml. per minute, but percutaneous renal biopsy revealed mild glomerulonephritis. After discontinuance of enovid-E and administration of a thiazide diuretic, the oedema disappeared, weight returned to normal, and hypertension abated. On subsequent visits to her physician up to January, 1967, her blood-pressure levels fluctuated between 130/90 and
150/100. Introduction
at
The
10 weeks, and 132/80 at 121/2 weeks. Orthonovum was then restarted. The patient gained 3 lb. in weight, and 4 weeks later her blood-pressure was 160/100. The drug was discontinued, and 9 weeks later the blood-pressure 6
was
REFERENCES
Andros, G., Harper, P. Endocr. 25, 1067.
accompanying figure.
Case 4 A
42-year-old woman had had 5 uneventful pregnancies. In hypertension, proteinuria, or oedema present. Her mother was known to have hypertension, and both parents had
none was
suffered strokes. In 1963 she was started on orthonovum. In August, 1965, she was referred to North Carolina Memorial Hospital for evaluation of recently discovered hypertension with blood-pressure consistently around 200/110 mm. Hg. Investigations revealed no cause for her hypertension. Orthonovum was discontinued, and a mild antihypertensive agent (’ Ser-Ap-Es’) was prescribed. The blood-pressure Case 1: systolic (x) and diastolic (o) bloodpressure related to intake of oral contraceptive.