718

The most favoured radiopharmaceuticals are preparations of thallium-201 and-technetium-99m. Thallium and other potassium analogues are taken up by the normal myocardium, so that an infarct of any age or a region of hypoperfusion is shown as an area of absent or reduced activity ("cold spot").' 2 Technetium is taken up by damaged tissue so that an acute infarct is shown as a positive image ("hot spot"). This artificial and versatile isotope (half life 6 hours) may be used as sodium pertechnetate or tagged to red cells or serum albumin when an intravascular label is required; or to tetracycline,3 polyphosphonate, or pyrophosphate when tissue uptake is being measured. Technetium-99m polyphosphate was first employed in studying bone,4 but in 1974 Bonte and colleagues at Dallas reported the use of technetium-99m stannous pyrophosphate for myocardial imaging.5 A new preparation, technetium-99mimidophosphonate, has now been used experimentally and clinically and claimed as the agent of choice.6 7 These substances appear to be incorporated, probably with calcium,8 in or near the mitochondria of damaged cells in the form of hydroxyapatite crystals9 10 and accumulate mainly in the tissue at the edge of the infarct. Imaging with technetium has been extensively used by the Dallas group,"1-15 who have studied over 3500 patients.14 The optimal time for the investigation is between 24 and 48 hours after the onset of the infarct, with scanning one to two hours after the injection, usually in three projections. For maximal information the procedure may be repeated in a day or two, or successive imaging with thallium-201 and technetium-99m may be used.'3 16 Other variants are possible, such as combining static and dynamic imaging.17 A positive result with a technetium scan may usually be obtained up to six days after the infarct; after this the image begins to fade, though occasionally it persists for weeks or months. Assessing the image is subjective, and the grading (customarily 0 to 4) refers to the visibility of the image and not to its size.15 Unequivocally positive scans are present in some 90-95% of ECG-proved transmural infarcts, where a localised area of uptake is seen; in subendocardial infarction the images are less intense and usually diffuse, so that the necrosis can seldom be localised anatomically." Uptake has also been observed in patients with stable'8 and unstable'9 angina and with valve calcification, ventricular aneurysm, or cardiomyopathy, and even after direct current shock.20 The scintigram has not proved reliable in assessing the size of an infarct, largely because the uptake of radioactivity depends on blood flow and is not proportional to the volume of the infarct.2' In assessing the role of technetium scanning'4 15 21-23 we have to remember the conventional methods of diagnosing myocardial infarction. Thus in most patients the findings on serial electrocardiographs and measuring serum enzyme concentrations (together with necropsy findings) are the standards by which imaging or scintigraphy must be judged. Doubt whether myocardial infarction has occurred arises most often in patients with old infarction, left bundle branch block, subendocardial infarction, and after operation,24 when the serum enzyme concentrations are raised because of tissue trauma. In these cases the physician will hope for the most help, and he will further ask whether the scintigram can determine the cause of prolonged angina in acute coronary insufficiency, perhaps by demonstrating areas of necrosis too small or too diffuse to be detected by routine investiga-

tions.'9 Technetium preparations are cheap and safe, but gamma cameras are expensive, and few medical units have them.

BRITISH MEDICAL JOURNAL

9 SEPTEMBER 1978

Care in technique and caution in interpretation are required for reliable results.15 20 Bedside scanning is the icing on the cake of diagnosis of an infarct, and those physicians who do not have it should not feel too deprived: the information obtained by scintigraphy has still to be evaluated, and the clinician may yet find that the management of his patients will need no radical change. Zaret, B L, et al, New England Journal of Medicine, 1973, 288, 809. Wackers, F J Th, et al, British Heart Journal, 1975, 37, 741. 3Holman, B L, et al, American Journal of Cardiology, 1974, 33, 144. 4Subramanian, G, et al, Radiology, 1972, 102, 701. 5 Bonte, F J, et al, Radiology, 1974, 110, 473. 6 Ell, P J, et al, British Heart_Journal, 1978, 40, 226. 7Joseph, S P, et al, British Heart3Journal, 1978, 40, 234. 8 Shen, A C, and Jennings, R B, American Journal of Pathology, 1972, 67, 441. 9 D'Agostino, A N, and Chiga, M, American J7ournal of Clinical Pathology, 1970, 53, 820. 10 Coleman, R E, et al, American Journal of Cardiology, 1977, 39, 55. 11 Willerson, J T, et al, Circulation, 1975, 51, 436. 12 Willerson, J T, et al, Circulation, 1975, 51, 1046. 13 Parkey, R W, et al, Journal of Nuclear Medicine, 1976, 17, 771. 14 Willerson, J T, et al, J'ournal of the American Medical Association, 1977, 238, 1665. 15 Parkey, R W, et al, Seminars in Nuclear Medicine, 1977, 7, 15. 16 Henning, H, et al, American Journal of Cardiology, 1977, 40, 147. 17 Kan, M K, Hopkins, G B, and Carroll, C F X, JIournal of the American Medical Association, 1977, 238, 1637. 18 Mason, J W, et al, American Journal of Cardiology, 1977, 40, 1. 19 Donsky, M S, et al, British Heart Journal, 1976, 38, 257. 20 Ahmed, M, et al, American Journal of Cardiology, 1977, 39, 50. 21 Marcus, M L, and Kerber, R E, Circulation, 1977, 56, 337. 22 Cowley, M J, et al, Circulation, 1977, 56, 192. 23 Berman, D S, et al, American Journal of Cardiology, 1977, 39, 341. 24 Righetti, A, et al, American Journal of Cardiology, 1977, 39, 43. 1

2

Link between hepatoma and hepatitis B Though rare in Western countries, hepatocellular carcinoma (hepatoma) is common in Africa and Asia. Of the various possible genetic and environmental factors that have been implicated, the most important are aflatoxins and hepatitis B virus, and a recent international workshop' discussed the implications of the link between the latter and hepatoma. In 1970 Vogel et al,2 using relatively insensitive techniques, found that 40% of their patients with hepatomas had hepatitis B surface antigen (HBsAg) in their serum. The proportion was highest in young patients without underlying cirrhosis (7000 of those under 30) and lowest (17%) in patients over 50. In a British study of 17 patients with HBsAg-positive chronic liver disease of at least six months' duration five of the patients developed hepatoma.3 All were of Mediterranean stock. Soon afterwards an incidence of 31% of HBsAg was reported in patients with hepatoma from Athens.4 Not surprisingly, as more sensitive techniques such as radioimmunoassay and haemagglutination have come into use, much higher rates have been reported from series in Taiwan,5 South African blacks,6 Greece,7 Thailand,8 Senegal,9 Uganda,2 and South Vietnam10-areas where at least 700 of the normal population are HBsAg carriers. HBsAg has been found less frequently with hepatoma in series in France and the United States, where HBsAg carriers are far less common.11 12 Furthermore, Maupas et al13 found antibodies to the hepatitis B core antigen (anti-HBc) in 9500 of African and Asian patients with hepatoma and suggested that some patients may continue to produce core antigen but not surface antigen: thus screening for hepatitis B virus by HBsAg assay alone may

BRITISH MEDICAL JOURNAL

give false-negative results. Kubo et al4 found anti-HBc in 81% of over 200 sera from patients with hepatoma, though only 52%/" were HBsAg-positive. If hepatitis B virus causes hepatoma by initiating a chain of events in which active hepatitis leads to chronic hepatitis, cirrhosis, and eventually hepatoma then HBs-antigenaemia would be expected to be more common in hepatoma secondary to cirrhosis than in hepatoma unrelated to cirrhosis. This has in fact been found in most series. In a recent retrospective pathological study of hepatoma from California fewer than 1% of non-cirrhotic patients with hepatoma had markers of hepatitis B virus infection, whereas 73% of patients with cirrhosis had HBs antigenaemia.15 Admittedly, such a difference has not been found in major series from Britain and the United States.10 16 Susceptibility to hepatoma may be governed not only by risk of exposure to virus but also by the virulence of the virus, the tolerance of the host, the duration of infection, and nutritional and immunological factors. Various microtoxinsmost prominently aflatoxin, an aspergillus metabolite-have been implicated in cancer of the liver.'7 There are geographical parallels between the incidence of hepatoma and both the frequency of hepatotoxins contaminating the diet and the prevalence of hepatitis B infection or carriage. This suggests cocarcinogenesis, with two factors necessary to produce the cancer. In some countries, such as Egypt, there is a high rate of hepatitis B infection but hepatoma is uncommon: failure to find evidence that aflatoxin is contaminating food in these countries would support the hypothesis. Liver cancer, then, may result from chronic exposure to hepatocarcinogens, though it may also occur in an infected but otherwise normal liver. A hepatitis B virus vaccine given at an early age may be a means of preventing infection in endemic areas. Eliminating carriage of hepatitis B virus in the normal population would then lead to fewer cases of hepatoma. The presence of HBsAg does not, however, prove that hepatitis B virus causes the tumour, and other possibilities need to be considered. For example, the development of hepatocellular carcinoma might simply activate a latent hepatitis B virus, with production of surface or core antigen in infected cells. A recent survey of a normal Scottish population found that 7-500 have anti-HBs antibody, suggesting latent or previous infection.'8 Rates of latent infection may vary in different countries throughout the world. Alternatively, HBs-antigenaemia may indicate a defective immune response, resulting from insult by the same toxin that is responsible for hepatocarcinogenesis; thus aflatoxins have immunosuppressive

actions.'7 19 Finally, is HBs-antigenaemia in patients with hepatoma of prognostic importance and related to their clinical course? Recently Kubo et al14 have confirmed earlier reports20 that the duration of chronic liver disease before hepatoma is detected is significantly shorter in HBsAg-positive than in HBsAgnegative patients (four years compared with six years). Survival after tumour detection, however, was not significantly related either to the presence of HBsAg or to the duration of the previous liver disease. Ziegler, J L, et al, Journal of the National Cancer Institute, 1978, 60, 717. Vogel, C L, et al, Lancet, 1970, 2, 621. 3 Sherlock, S, et al, Lancet, 1970, 1, 1243. 4 Hadziyannis, S, et al, Lancet, 1970, 2, 100. 5 Tong, M J, et al, Annals of Internal Medicine, 1971, 75, 687. 6 Kew, M C, et al, Cancer, 1974, 34, 539. 7 Theodoropoulis, G, Archimandritos, A, and Angelopoulos, B, Annals of Internal Medicine, 1975, 82, 809. 8 Chainuvati, T, Viranuvatti, V, and Pongpipat, D, Gastroenterology, 1975, 68, 1261. 2

719

9 SEPTEMBER 1978

Prince, A M, et al, International Journal of Cancer, 1975, 16, 376. Welsh, J D, et al, Gastroenterology, 1976, 70, 392. Prince, A M, et al, Lancet, 1970, 2, 717. Alpert, M E, and Isselbacher, K J, Lancet, 1971, 2, 1087. 13 Maupas, P, et al, Lancet, 1975, 2, 69. 14 Kubo, Y, et al, Gastroenterology, 1978, 74, 578. 15 Peters, R L, Afroudakis, A P, and Tatter, D, American Journal of Clinical Pathology, 1977, 68, 1. 16 Johnson, P J, et al, Gut, 1978, in press. 17 Aleksandrowicz, J, et al, Przeglad Lekarsky, 1971, 28, 689. 18 Turbitt, M L, et al, Journal of Clinical Pathology, 1977, 30, 1124. 19 Savel, H, et al, Proceedings of the Society for Experimental Biology and Medicine, 1970, 134, 1112. 20 Obata, H, et al, in Hepatic Scientific Memoranda H881. Buffalo, Calspan Corporation, 1975. I

10

1 12

Radioimmunoassay of serum prostatic acid phosphatase in prostatic cancer Earlier diagnosis of cancer of the prostate may become possible with the development of a radioimmunoassay for detection of the serum prostatic acid phosphatase. Biochemical estimation of the enzyme is in general use as an ancillary diagnostic procedure in suspected prostatic cancer and as an indicator of the response to treatment. Acid phosphatase is elaborated by adult prostatic acinar epithelium. When there is neoplastic proliferation, possibly with increased cellular permeability or other factors, more may be released into the circulation. The quantitative biochemical methods used to measure the concentration in the serum have been combined with refinements such as the 1-tartrate modification to exclude similar enzymes produced from other tissues or organs. Generally the results have given useful confirmation of the disease where there was local or metastatic spread but in earlier stages have proved less informative. Clinical experience has shown that values are significantly raised in only about a quarter of cases where the tumour remains confined to the prostate while 75%0 have raised values when there are metastases or extracapsular spread. This shortcoming may reflect the imprecision of the technique but is perhaps due to variations in the capacity of the neoplastic cells to sustain phosphatase production or to the defensive reaction of the tissues surrounding the tumour effectively limiting the entry of enzyme into the blood stream. A new method of radioimmunoassayl is probably more sensitive throughout the full range of pathological stages of the disease. The technique is complex: a specific antiserum is produced by the inoculation of female rabbits with purified acid phosphatase from adult human prostatic fluid; this is treated with suitably buffered bovine serum albumin and incubated with serum and l251-labelled antigen for 45 hours. The percentage of labelled antigen bound to antibody is counted and the concentration of unknown prostatic acid phosphatase determined by reference to a standard curve. From a preliminary trial of the technique in 600 normal men Foti and his colleagues1 showed that after puberty the level of the enzyme was little influenced by age. In a subsequent series of 50 normal controls (averaging 64-5 years) the values ranged between 3-5 and 6-6 ng per 0-1 ml serum. Using the upper limit as a guideline, they compared the results with those of standard enzyme assay in 113 patients with prostatic cancer and 187 controls with various diseases. The radioimmunoassay findings showed a significantly increased number of high values in the group with prostatic cancer which

Link between hepatoma and hepatitis B.

718 The most favoured radiopharmaceuticals are preparations of thallium-201 and-technetium-99m. Thallium and other potassium analogues are taken up b...
530KB Sizes 0 Downloads 0 Views