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The Diagnosis and Staging of Hypocortisolism in Progressing Autoimmune Adrenalitis

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The Diagnosis and Staging of Hypocortisolism in Progressing Autoimmune Adrenalitis GI MUCOSAL BARRIER 86 1 15. Lowry. 0. H.. Rosebrough. N. J.. Farr. A. L., and Randall, R. G.: Protein polarization studies of the small intestinal microvillus membrane during measurement with the folin phenol reagent. J. Biol. Chem., 193: 265 (1951). development. Gastroenterology. 82: I 176 (1982). 16. McDonald. N. M., Bruns, D. E., and Jarett, L.: Characterization of calcium 27. Schlatz, L. and Marinetti. G. V.: Calcium binding to the rat liver plasma binding to adipocyte plasma membrane. J. Biol. Chem., 251: 1354 (1976). membrane. Biochim. Biophys. Acta. 290: 70 (1972). 17. Melcher, D. L. and Steim, J. M.: Thermotropic transitions in biomembranes. 28. Tsuboi, K. K., Schwartz, S. M.. Burrill. P. H., Kwong, L. K., and Sunshine. Ann. Rev. Biophys. Bioeng., 5: 205 (1976). P.: Sugar hydrolysis of the infant rat intestine and their arrangement of the 18. Messer, M. and Dahlquist, A.: A one step ultramicromethod for the assay of brush border membrane. Biochim. Biophys. Acta. 554: 234 (1979). intestinal dissacharidases. Anal. Biochem., 14: 376 (1966). 29. Udall, N. J., Pang. K., Fritze. L., Kleinman. R.. and Walker. W. A,: Develop- 19. Nicholson, G. L., Poste, G., and The, J.: Dynamic aspects of cell surface ment of gastrointestinal mucosal barrier. I. The effect of age on intestinal organization. Ed: G. Poste and G. Nicholson. pp. 1-73 (North Holland, permeability to macromolecules. Pediat. Res., 15: 24 1 (1 98 1). Amsterdam 197 1). 30. Udall. J. N.. Colony. P., Fritze, L.. Pang, K.. Trier, J. S. and Walker, W. A,: 20. Nuston, C., Pangborn, W., Nir, Z., and Papadjopoulos, D.: Specificity of Ca++ Development of gastrointestinal mucosal barrier. The effect of natural versus and Mg" binding to phosphatidyl serine vesiclesand resultant phase changes artificial feedings on intestinal permeability to macromolecules. Pediatr. of biliary in membrane structure. Biochem. Biophys. Acta, 506: 281 (1978). Res., 15: 245 (1981). 2 1. Palmer, R. F. and Posey. V. A.: Calcium and adenosine triphosphate binding 31. Walker, W. A,, Cornell, R.. Davenport. L. M. and Isselbacher, K. G.: Macro- to renal membranes. J. Gen. Physiol., 55: 89 (1970). molecules absorption: Mechanism of horseradish peroxidase uptake and 22. Pang, K. Y., Bresson, J. L., and Walker, W. A,: Development of the gastroin- transport in adult and neonatal rat intestine. J. Cell Biol., 54: 195 (1972). testinal barrier Ill. Evidence for structural differences in microvillus mem- 32. Warshaw, A. L., Walker, W. A.. Cornell. R. and Isselbacher, K. J.: Small brane from newborn and adult rabbits. Biochim. Biophys. Acta, 727: 201 intestine permeability to macromolecules: Transmission of horseradish per- (1983). oxidase into mesenteric lympyh and portal blood. Lab. Invest., 26: 675 23. Sauerheber, R. D., Lewis, U. J., Esgate, G. A., and Gordon, L. M.: Effect of (1971). calcium insulin and growth hormone on membrane fluidity. A spin label 33. Current address: Department de Pediatrie, Hopital des Enfants Malades. Paris. study of rat adipocyte and human erythrocyte ghosts. Biochem. Biophys. France. Acta. 597: 294 (1980). 34. Received for publication Dr. Kam-Yee Pang, Pediatric Gastrointestinal and 24. Scatchard. G.: Attractions of proteins for small molecules and ions. Ann. N. Nutrition Unit. Massachusetts General Hospital, Boston, MA 021 14. Y. Acad. Sci., 51: 660 (1949). 35. Supported by research grants from the National Institute of Health (AM16269. 25. Schmitz, G., Preizer, H.. Malstracci, D., Ghost, B. K., Cerda, J. G., and Crane, HD12437 and GM2 1700) Dr. Pang is a trainee in Gastrointestinal Research R. K.: Purification of the human intestinal brush border membrane. (T32-AM079 I). Biochim. Biophys. Acta. 323: 98 (1973). 36. Received for publication August 26, 1982. 26. Schwarz. S. M., Hostetler, B.. Ling, E.. Lel, L., and Walkins, G. B.: Fluorescence 37. Accepted for publication March 23, 1983. 003 1-3998/83/17 1 1-086 1$02.00/0 PEDIATRIC RESEARCH Vol. 17, No. 1 1. I983 Copyright O 1983 International Pediatric Research Foundation, Inc Prin1c.d in L: S ..I. The Diagnosis and Staging of Hypocortisolism in Progressing Autoimmune Adrenalitis SEPPO LEISTI,'32' PEKKA AHONEN, AND JAAKKO PERHEENTUPA The Children's Hospital, University of Helsinki, Helsinki, Finland Summary 4dAT, 4-day ACTH test 2hAT, 2-h ACTH test The course of development of hypocortisolism was studied in 17-OGS, 17 oxogenic steroids 20 patients with autoimmune polyendocrinopathy-candidosis-ec- RIA, radioimmunoassay todermal dystrophy (APECED) for 1.3-9.3 years during which time the patients underwent at least three 2-h ACTH tests (2hAT). A slow progression of the disease was evident and could be staged. The earliest indicators of incipient failure were sub- Autoimmune adrenalitis is a major cause of Addison's disease. normality of the 2-h corfiisol level alone or with subnormality of In patients with polyendocrine deficiency diseases and their the 2-h increment. The increment was then abolished. A normal siblings, frequent testing of cortisol reserve is essential for early basal level was maintained longer. Longer forms of the ACTH detection of failure of cortisol secretory capacity. Long lasting tests produced normal responses even after the early stages of ACTH tests are impractical, because they entail hospitalization. failure. A constantly elevated ACTH concentration and low cor- Furthermore, such tests may not be sensitive enough to detect tisol/ACTH ratio in plasma were likewise signs of advanced incipient failure. To our knowledge, no systematic study has hypocortisolism. Current criteria of primary hypocortisolism are appeared on the progression of hypocortisolism in adrenalitis. thus indicators of the late stages of failure only. The presence of Neither have criteria been established for early stages of primary circulating adrenocortical antibodies is predictive of hypocorti- hypocortisolism. Such criteria would be important for the safety solism. Some patients had normal 2hAT responses, but anti- of individuals at risk. We have used an ambulatory 2-h ACTH bodies and subnormal cortisol/ACTH ratios. This may represent test (2hAT) (1 3) for both detection and follow-up of progression a state of compensatory activation of the hypothalamic-pituitary- of hypocortisolism in our large series of patients with APECED adrenocortical axis. (18, 23). The 2hAT was clearly more sensitive than the 4dAT for the detection of incipient failure and even more sensitive Abbreviations than determinations of plasma ACTH. Our experience with these APECED, autoimmune polyendocrinopathy-candidosis-ectoder- patients calls for a revision of the current diagnostic criteria of ma1 dystrophy Addison's disease. 862 LElSTI ET AL. SUBJECTS AND METHODS A 2hAT performed on the morning after the 4dAT is called a primed 2hAT. The result of this test was compared with the Of a total of 40 patients with APECED managed by us in result of a 2hAT given on the morning before a 4dAT. 1970-1980 (23), 20 are the subjects of this report (Table I). All Laboratory methods. Plasma 1 I-hydroxycorticoids (hereafter patients included in this study had been followed for at least 1 referred to as a cortisol) were determined by a two-point fluo- year and with a minimum of three 2hATs. The median interval rometry method (1 3) with a between-assay coefficient of varia- between tests was 0.8 (range, 0.1-3.3) years. At the start of the tion of 4.4%for levels between 15-72 ~gJdl(0.47-2.0pM). The follow-up none of the 20 patients was substituted for cortisol and precision of the method was strictly controlled and the method 17 of them had normal adrenocortical function. The diagnosis was unchanged during the period of this study. Its accuracy was of APECED was based on the presence of at least two of the evaluated by parallel determination of cortisol with a specific following features (or one if a sib had at least two): mucocuta- RIA in 34 samples (ranges, 5.4-47 pg/dl by RIA). The correlation neous candidosis, hypoparathyroidism, hypoadrenocorticism, was high (r = 0.96) with linear regression: ~0rtis01~~~= 0.75 and ectodermal dystrophy (19, 23) (enamel hypoplasia, onychia cortisolFl + 5.7 pg/dl. Urinary 17-OGS were determined by punctata). Fourteen of the patients had circulating adrenocortical colorimetry (30), and reported as mg .m-' .day-'. Plasma ACTH antibodies. A group of twenty-five children with hypopituitarism was assayed with a radioimmunoassay kit (Sorin, Biomedica, including ACTH deficiency were also given a total of 34 2hATs 13040 Saluggia, Vercelli, Italy). Blood samples were chilled on to allow comparison of the results during primary and secondary ice water, and plasma was separated without delay. N-methyl- hypocortisolism. The diagnosis of ACTH deficiency was based maleinimide was added to an 1 mM concentration, and the on subnormal plasma cortisol response to at least two insulin mixture was stored at - 18°C until assayed for ACTH. The limit tests. Most patients also had metyrapone tests, always with a of sensitivity was 10 nglliter, and basal levels of >I00 ng/liter subnormal response. Of the hypopituitary patients, 18 had a were considered elevated. For anti-adrenocortical antibodies hypothalamic tumor, four had been born in breech presentation, (hereafter referred to as antibodies), sera were tested by an one had sequelae of subdural effusion, and two cases were indirect imunofluorescence method (1 1). idiopathic. Statistical anulvsis. Means, S.D.s, and S.E.M.s of endocrine Cortisol substitution was given as oral cortisol, 7.5-10 mg values were calculated from log transformed data; hence, all daily divided in three doses. This substitution was stopped on means are geometric, and S.E.M.s are given as percentages (28). the day preceding the test and resumed upon completion of the Normal response criteria for the 2hAT were based on results for test. Adequate substitution therapy was given for any associated 30 healthy children aged 2.8-18.4 years.
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