Adrenocorticotropic hormone receptor-blocking immunoglobulins in serum from patients with Addison's disease: a reexamination.

The presence of antibodies inhibitory to ACTH-stimulated cortisol secretion was investigated in patients with Addison's disease. In preliminary experiments, immunoglobulin G (IgG) samples from patients with Addison's disease and control subjects were prepared using diethylaminoethyl-cellulose ion exchange chromatography. Twelve of 29 Addison's IgGs and 1 of 3 control IgGs inhibited ACTH-stimulated cortisol secretion in an in vitro guinea pig adrenal cell bioassay. All but 1 of the samples that inhibited ACTH-stimulated cortisol secretion also inhibited dibutyryl cAMP-stimulated steroidogenesis. IgGs purified by protein-G immunoaffinity were similarly screened for inhibition of ACTH-stimulated cortisol secretion; samples from 5 controls and 5 patients with Graves' disease were without effect, and IgGs from only 2 of 25 patients with Addison's disease decreased ACTH bioactivity (by < 12%). The effects of the IgGs on ACTH bioactivity in vitro were not concentration dependent. Our results suggest that Addison's disease is not caused by circulating antibodies to the ACTH receptor. The inhibitory effects seen with IgG prepared by diethylaminoethyl ion exchange chromatography were most likely attributable to the effects of non-IgG components in the preparations.

Hypermanganesemia in long-term intravenous nutrition and chronic liver disease.

BACKGROUND: Hypermanganesemia and cholestatic liver disease are both recognized complications of long-term IV nutrition. Manganese is primarily excreted in bile, and recent studies have indicated that manganese toxicity may play a role in the pathogenesis of IV nutrition-associated cholestasis. METHODS: Whole blood and plasma manganese concentrations were measured in patients receiving long-term home IV nutrition (HIN, n = 30). Whole blood manganese concentrations also were measured in patients with chronic liver disease (CLD, n = 10) and control subjects (n = 10). RESULTS: Whole blood manganese concentrations of all CLD patients were within the reference interval (73 to 210 nmol/L) and were not different from those of the control group (151 +/- 44 nmol/L, CLD vs 155 +/- 35 nmol/L, control; not significant), despite the presence of cholestasis. In contrast, whole blood manganese concentration was increased (>210 nmol/L) in 26 patients, and plasma manganese concentration increased (>23 nmol/L) in 23 of the patients receiving HIN. None of the patients exhibited neurologic signs of manganese toxicity. There was no correlation between whole blood manganese concentrations and markers of cholestasis, IV manganese intake, or duration of HIN. However, plasma manganese concentration correlated both with average weekly IV manganese intake (r = .44, p = .02) and with gamma-glutamyl transferase (r = .43, p = .02) and alkaline phosphatase activities (r = .55, p = .003). CONCLUSIONS: Cholestatic liver disease does not appear to contribute to increased whole blood manganese concentrations in patients not receiving HIN. Plasma manganese concentrations in patients receiving HIN reflect recent manganese exposure and impaired excretion where cholestasis is present. The lack of relationship between plasma and whole blood manganese concentrations suggests that factors other than manganese intake and excretion affect intracellular concentrations.

Hypoxia-stimulated glycerol production from the isolated, perfused rat heart is mediated by non-adrenergic mechanisms.

Factors controlling hypoxia-induced myocardial glycerol release were studied in isolated, perfused rat hearts. A constant coronary flow rate 10 ml g-1 min-1 was maintained. The perfusion buffer was gassed with O2-N2 mixtures containing 5% CO2. The O2:N2 ratios were normoxia 95:0, hypoxia 30:65, and severe hypoxia 10:85 (v/v). Glycerol and lactate release were stimulated during a 30-min period of either hypoxia or severe hypoxia but remained constant during normoxia. Tissue glycerol-3-phosphate levels were increased after 30 min hypoxia compared with after a similar period of normoxic perfusion (p < 0.01) and further increased after severe hypoxia (p < 0.01 vs hypoxia). beta-Adrenoceptors remained sensitive to isoprenaline during hypoxia, demonstrated by an increase in glycerol release over a 30-min period of isoprenaline infusion from 897 +/- 317 to 1771 +/- 307 nmol g-1 wet weight (p < 0.05). The isoprenaline-induced increase in glycerol release during hypoxia was inhibited by both atenolol and timolol (1 x 10(-5) M). In contrast, beta-adrenoceptor blockade using these drugs failed to reduce glycerol release induced by either hypoxia or severe hypoxia. Both drugs attenuated the rise in glycerol-3-phosphate during hypoxia. Chronic denervation by pretreatment with 6-hydroxydopamine reduced hypoxia-stimulated glycerol release by only 30%. Thus, a major part of hypoxia-induced glycerol release is mediated by non-adrenergic mechanisms. The results of this study bring into question the validity of the use of glycerol production during hypoxia as a reliable measure of myocardial lipolysis.

Pitfalls in the use of thyrotropin concentration as a first-line thyroid-function test.

Measurement of thyrotropin concentration alone as a first-line thyroid-function test fails to indicate hypopituitarism in a number of patients. Using a combination of thyrotropin and thyroxine assays, we analysed 56,000 tests for a population of 471,000 over 12 months. 15 patients with clinically unsuspected hypopituitarism were detected, indicating that the occurrence of hypopituitarism might be underestimated.