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microsomal reactive autoantibody.2 The anti-GOR autoantibody described by Mishiro et al might be produced in a similar fashion, via the association of an HCV protein with a self-protein. If this were the case and the autoantibody initiated liver cell necrosis, HCV might be capable of producing autoimmune liver disease, either transient or long-lasting, depending on the duration of the inciting infection. The observation that 60% of patients with type 2 autoimmune chronic active hepatitis3 (a subgroup of autoimmune chronic hepatitis defmed by the presence of a liver/kidney microsomal reactive antibody in serum) are positive for HCV antibodies also raises this possibility. Confirmation of Mishiro et al’s findings would suggest that HCV might well initiate some types of autoimmune chronic hepatitis. Nevertheless, it must be remembered that the existing anti-HCV test (Ortho) gives false-positive results in patients with high serum globulin concentrations.4 The anti-GOR antibody warrants further investigation as a possible means of establishing the relation between hepatitis viruses and induction of autoimmune liver disease. 1. Crivelli O, Lavarini C, Chiaberge E, et al. Microsomal autoantibodies in chronic infection with the HBsAg associated (&dgr;) agent. Clin Exp Immunol 1983; 54: 232-38. 2. Beaune Ph, Dansette PM, Mansuy D, et al. Human anti-endoplasmic reticular autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. Proc Natl Acad Sci USA 1987; 84: 551-55. 3. Lenzi M, Ballardini G, Fusconi M, et al. Type 2 autoimmune hepatitis and hepatitis C virus infection. Lancet 1990; 335: 258-59. 4. McFarlane IG, Smith HM, Johnson PJ, Bray GP, Vergani D, Williams R. Hepatitis C virus antibodies in chronic active hepatitis: pathogenetic factor or false-positive result? Lancet 1990; 335: 754-57.

PROMOTING HEALTH RESEARCH FOR DEVELOPMENT Should the paradigm for medical research in developing countries be changed, or at least broadened? This question lies behind the report of the Commission on Health Research for Development. Lancet readers will be aware2,3 that the Commission was established over two years ago and that most members come from developing countries. The Commission has reported on time and has originated an approach, a survey, an analysis, and some clear recommendations coupled to a definite agenda for the future. This agenda was developed further at a Nobel conference held in Stockholm earlier this year.4 The Commission’s starting point is that health is a neglected investment in development (not simply a welfare or consumption item) and research is a neglected investment in health so far as developing countries are concerned. If development is to be more equitable, health and health research must play a greater part. The distribution of research effort is highly skewed: 93% of years of useful life lost due to disease are in developing countries and are due to health problems that receive only 5% of the world’s health research funding. The Commission’s detailed survey of spending on health research produced some unexpected findings. Developing countries spend substantial amounts of their own meagre funds on research-four times more than reaches them from industrialised countries for that purpose-but three-quarters of this indigenous expenditure is by only eight large developing countries. Research is a necessity for progress, not a luxury. Every country, no matter how poor, needs to have the capacity for health research to provide a rational basis for improving its

health care. "To understand its own problems, to enhance the impact of limited resources, to improve health policy and management, to foster innovation and experimentation, and to provide the foundation for a stronger developing country voice in setting international priorities, the establishment of an appropriate health research base in each developing country, no matter how poor, is essential. The Commission has named such a base essential national health research (ENHR)." Sound policy and management decisions-even more crucial when the per caput health budget is tiny than when it is large-need ENHR so that each country understands its own difficulties and how best to tackle them. The most neglected aspect is country-specific research that can inform decision-making-to define the health of the nation, shape health policy, and improve the operation of services and programmes. Research capacity is especially necessary in epidemiology and the social sciences applied to health. At least 2 % of national health expenditure should be devoted to support of ENHR and to building up and maintaining research capacity. International collaborative networks of health research workers should be developed if understanding is to be pooled and small national groups supported, and more long-term financial support is needed from international sources. Programmes for building national research capacity and measured in tens of years are needed more than short-term projects. Lastly, some international way should be found to promote funding and scientific support for health research. Is ENHR merely the latest international agency buzzword? Certainly everyone doing useful research in the third world can fmd a niche for that research in ENHR, but there is more to it than that. Surprisingly, it commands more immediate and enthusiastic acceptance within the third world than in the west’s heavily structured medical research culture. First, it is about a process-ENHR aims to bring together research workers, policy-makers from the health ministries and beyond, and members of the health professions of each developing country to sort out their priority needs for research in terms of both the problems and the approaches. The agenda for research needs to be indigenous rather than imposed by outside donors (however well-intentioned). Second, medical research on its own is unlikely to provide satisfactory solutions. Relevant questions may range from how the medicine bill is to be financed to how can one prevent the ill health associated with transmigration. Solutions may come from policy change as well as from improved disease control techniques. Third, it follows that such research will need to be multidisciplinary; no approach is precluded. Inevitably there will be questions about freedom of researchers, but this is about research which must be done if countries are to control their own health destiny-about what is now being left undone rather than about restrictions. Is this all utopian idealism? It seems not. Countries as diverse as Mozambique, Mexico, Thailand, Zimbabwe, and the Philippines have created groups to implement ENHR. The innovations proposed have potentially far-reaching consequences. The crucial next step will be to maintain and develop these activities, to enable them to happen in other interested countries, and to document the process so that each group may learn from the others. Progress will depend on at least three things-leaders with vision in each country, national political will, and an effective international funding system. The first two are emerging rapidly in several

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countries; the need for the last is acute and reliant on donor support and the efforts of a task force set up to carry forward the Commission’s work. 1. Commission on Health Research for Development. Health research: essential link to equity in development. New York: Oxford University Press, 1990. ISBN 0-195208382. 2. Editorial. Commissioning international health. Lancet 1987; ii: 1064-65. 3. Anon. Independent International Commision on Health Research for Development. Lancet 1987; ii: 1076-77. 4. Health Research for Development. Karolinska Institute Nobel Conference no 15. SAREC conference report 1990:1. Obtainable from SAREC, Klarabergsgatan 23, Box 16140, 10323 Stockholm, Sweden.

CRH TEST IN THE 1990s Almost 10 years have elapsed since the isolation of the 44-aminoacid ovine hypothalamic corticotropin-releasing hormone, CRH. This hormone stimulates the release of corticotropin from the anterior pituitary.1 Clinical studies soon showed that an intravenous injection of CRH led to a rise in both plasma corticotropin and serum cortisol concentrations in normal volunteers.2 Initial enthusiasm for the use of the CRH test in the diagnosis of Cushing’s syndrome3-5 began to wane when it was realised that there was a considerable overlap between a normal and an abnormal corticotropin and cortisol response. However, subsequent studies of larger groups of subjects have allowed 6 a thorough evaluation of responses in normal individuals obese subjectsand patients with depression8jn addition to those with Cushing’s syndrome,9-12 and the importance of the CRH test in the differential diagnosis of Cushing’s syndrome is now established. The introduction of new methods of treatment for Cushing’s syndrome during the past decade, especially microsurgery for pituitary adenomas,13 has highlighted the importance of a precise anatomical diagnosis. The CRH test has no role in the initial diagnosis, which is most easily achieved by the finding of a raised 24-hour urinary free cortisol concentration,14 but it helps to determine the origin of the hypercortisolism-pituitary overproduction of

corticotropin (Cushing’s disease), ectopic corticotropinproducing tumour, or cortisol production from an adrenal adenoma. Experience with the CRH test has confirmed that the vast majority of patients with Cushing’s disease have either an exaggerated or a normal corticotropin and cortisol response whereas patients with ectopic corticotropin production or an adrenal tumour usually do not respond.9--12 Blood sampling and assay of corticotropin is a complex and costly procedure, so it is fortunate that in the diagnosis of Cushing’s disease the cortisol response to CRH stimulation is more specific than the corticotropin response. 11,12,15 The CRH test can be reliably carried out in an outpatient clinic. Nevertheless, the overall sensitivity of the test in determining the cause of Cushing’s.syndrome in all the studies conducted so far is no greater than 90%, although specificity is about 95%.9-12 Thus, use of CRH as the single test for differential diagnosis would lead to the incorrect classification of a small but important group of patients. The combination of a CRH test with a high-dose dexamethasone suppression test (2 mg dexamethasone 8-hourly for 48 h followed by measurement of serum cortisol) provides almost 100% sensitivity and specificity for the diagnosis of Cushing’s disease.9-11 Patients with an equivocal CRH response will show suppression after dexamethasone suppression whereas those with equivocal dexamethasone suppression will show either a normal or an exaggerated

cortisol release to CRH. By contrast, there is no response to CRH or dexamethasone suppression in patients with In this group, an adrenal macronodular adrenal hyperplasia can be by a high-definition adrenal computed tomographic scan. A response to CRH virtually excludes the

ectopic corticotropin production. adenoma excluded

or

ectopic corticotropin syndrome. The original studies with CRH were carried out with the ovine hormone (oCRH), which is not now readily available for clinical use. Initial comparisons of oCRH with human CRH (hCRH) suggested pituitary-adrenal responses to lower than those to oCRH.16 In a more recent Faria and colleagues17 confirmed that the peak study, cortisol response was less with hCRH, but found that hCRH was more sensitive than oCRH in the differential diagnosis of Cushing’s syndrome. This study shows that it is important for endocrine units to define local standards not only for the dose of CRH administered (usually 100 µg) but also for the normal laboratory ranges for cortisol response. Overall, the CRH test has come of age for the 1990s, especially for distinguishing pituitary-led Cushing’s disease from ectopic corticotropin secretion. hCRH

were

1. Vale W, Speiss J, Rivier C, Rivier J. Characterisation of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and &bgr;-endorphin. Science 1981; 213: 1394-97. 2. Grossman A, Niewenhuyzen-Kruseman AC, Perry L, et al. New

hypothalamic hormone, corticotropin-releasing factor, specifically stimulates the release of adrenocorticotropic hormone and cortisol in man. Lancet 1982; i: 921-22. Lytras N, Grossman A, Perry L, et al. Corticotropin-releasing hormone: responses in normal subjects and patients with disorders of the hypothalamus and pituitary. Clin Endocrinol 1984; 20: 71-84. 4. Orth DN, De Bold CR, De Cherney GS, et al. Pituitary microadenomas causing Cushing’s disease respond to corticotropin-releasing factor. J Clin Endocrinol Metab 1982; 55: 1017-19. 5. Muller OA, Dorr HG, Hagen B, et al. Corticotropin-releasing factor [CRF]-stimulation test in normals and patients with disturbances of the hypothalamo-pituitary-adrenal axis. Klin Wochenschr 1982; 60:

3.

1485-91.

6. Young WF, Zinsmeister AR, Kao PC, Carpenter PC. Ovine corticotropin-releasing hormone stimulation test: normal value study. Mayo Clin Proc 1990; 65: 943-48. 7. Kopelman PG, Grossman A, Lavender P, et al. The cortisol response to corticotropin-releasing factor is blunted in obesity. Clin Endocrinol 1988; 28: 15-18. 8. Gold PW, Loriaux DL, Roy A, et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. N Engl J Med 1986; 314: 1329-35. 9. Nieman LK, Chrousos GP, Oldfield EH, et al. The ovine corticotropinreleasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing’s syndrome. Ann Intern -

Med 1986; 105: 862-67. 10. Hermus AR, Pieters GF, Pesman GJ, Smals AG, Benraad TJ, Kloppenborg PW. The corticotropin-releasing-hormone test versus the high-dose dexamethasone test in the differential diagnosis of Cushing’s syndrome. Lancet 1986; ii: 540-44. 11. Grossman AB, Howlett TA, Perry L, et al. CRF in the differential diagnosis of Cushing’s syndrome: a comparison with the dexamethasone suppression test. Clin Endocrinol 1988; 29: 167-78. 12. Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med 1990; 112: 434-44. 13. Melby JC. Therapy of Cushing’s disease: a consensus for pituitary microsurgery. Ann Intern Med 1988; 109: 445-46. 14. Burke CW, Beardwell CG. Cushing’s syndrome. Quart J Med 1973; 42: 175-204. 15. Suda T, Kondo M, Totani R, et al. Ectopic adrenocorticotropin syndrome caused by lung cancer that responded to corticotropinreleasing factor. J Clin Endocrinol Metab 1986; 63: 1047-51. 16. Nieman LK, Cutler GB, Oldfield RH, et al. The ovine corticotropinreleasing hormone [CRF] stimulation test is superior to the human CRH stimulation test for the diagnosis of Cushing’s disease. J Clin Endocrinol Metab 1989; 69: 165-69. 17. Faria MS, Kopelman PG, Besser GM, Grossman AB. A comparison of the effects of human and ovine corticotropin-releasing hormone-41 on the pituitary adrenal axis. Neuroendocrinology 1990; 52: P4.6 [abstr].

Promoting health research for development.

1415 microsomal reactive autoantibody.2 The anti-GOR autoantibody described by Mishiro et al might be produced in a similar fashion, via the associat...
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