Predicting relapse after transsphenoidal surgery for Cushing's disease.

Although selective transsphenoidal surgery is an effective treatment for pituitary-dependent Cushing's syndrome the definition of cure as distinct from improvement is unclear. Complete tumor removal should be associated with very low serum cortisol levels because of long-term suppression of normal corticotrophs but the optimum timing of this investigation after surgery has not been established. Eleven consecutive patients with surgical and histological confirmation of a corticotroph adenoma removed at transsphenoidal surgery for proven Cushing's disease were studied with 0900 h serum cortisol levels at 5-14 days and 6-12 weeks postoperatively. Patients were maintained on hydrocortisone 10 mg three times daily (final dose at 1800 h) pending recovery of the hypothalamic-pituitary axis which was assessed by periodic short tetracosactrin tests and continued remission of the condition was confirmed by low dose dexamethasone suppression testing. All patients achieved clinical resolution of their disease but four subsequently developed biochemical evidence of recurrence with incomplete suppression on low dose dexamethasone testing at 2-48 months after surgery. These patients had 0900 h serum cortisol levels of 124, 95, 186, and 265 nmol/L at 5-14 days and 334, 52, 130, and 240 nmol/L at 6-12 weeks postoperatively. The remaining seven patients, who are in remission after 8-83 (median 24) months of follow-up, demonstrated 0900 h serum cortisol levels of 30-75 (median 31) nmol/L at 5-14 days but lower levels at 6-12 weeks (< 20 nmol/L in three patients and 22, 30, 30, and 33 nmol/L in the remainder). In this series, serum cortisol measurements at 6-12 weeks after transsphenoidal surgery for Cushing's disease are lower than levels obtained within 2 weeks of surgery and appear to give better discrimination of continuing remission; levels less than 35 nmol/L suggest a favorable long-term outcome.

Outcome of gestational diabetes in Bengali Asians living in an east London health district.

The characteristics and outcome of pregnancy complicated by gestational glucose intolerance are described in a consecutive series of 69 Bengali Asian patients and a parallel group of 22 Caucasian patients. The Bengali patients were older and of higher parity than the Caucasians and more frequently required insulin therapy. However, the outcome of pregnancy was similar in terms of antenatal clinic attendance, the number of antenatal hospital admissions, glycaemic control, birthweight and mode of delivery. Of those patients who attended for postnatal glucose tolerance test, 20% of the Bengali population demonstrated persisting abnormality of glucose tolerance, whereas no abnormalities were evident in the Caucasian group. These findings are consistent with the high prevalence and early age of onset of non-insulin-dependent diabetes in Asian populations. The World Health Organisation (WHO) criteria for the diagnosis of impaired glucose tolerance proved insufficiently sensitive for the diagnosis of gestational diabetes. This was particularly demonstrated by four patients with apparently normal glucose tolerance by WHO criteria who subsequently required insulin therapy.

The production of immunoreactive alpha- and gamma-interferon by circulating mononuclear cells in type 1 diabetes.

Using a specific immunoradiometric assay method the in vitro alpha interferon response to polyinosinic:polycytidylic acid (poly-I:C) and the gamma interferon response to concanavalin A were measured in peripheral blood mononuclear cells from 11 healthy matched pairs of Type 1 diabetic patients and normal subjects. The alpha-interferon response to poly-I:C was significantly higher in the diabetic group (median 3.7 (range less than 1-25.7) u ml-1) than in the normal group (1.1 (less than 1-15.4) u ml-1, p less than 0.01). The mean gamma-interferon response to concanavalin A was 64.3 +/- 46.9 (+/- SD) u ml-1 in the diabetic patients and 49.4 +/- 18.5 u ml-1 in the normal group (NS). The higher alpha-interferon response to poly-I:C in the diabetic patients was not related to blood glucose concentration, HbA1, age of onset of diabetes, duration of diabetes, or islet cell antibody positivity, and may therefore indicate intrinsic hyper-responsiveness of circulating mononuclear cells in Type 1 diabetes.

Thyroxine replacement in post-radioiodine hypothyroidism.

Thyroxine replacement dose in 70 patients with post-radioiodine (for Graves' thyrotoxicosis) hypothyroidism was compared with that in 34 patients with autoimmune hypothyroidism matched for age and sex and diagnosed during the same period. Median replacement dose in the post-radioiodine group (100 micrograms daily) was significantly lower (P = 0.006) than in the autoimmune hypothyroid group (137.5 micrograms daily). Furthermore there was marked variation in the time elapsing from onset of post-radioiodine hypothyroidism to achievement of a given maintenance dose. These findings may be explained by persistence of non-TSH mediated thyroid function, after radioiodine therapy for Graves' thyrotoxicosis. The observations indicate the potential risk of overtreatment with thyroxine in post-radioiodine hypothyroidism unless the dose is carefully titrated against serum TSH levels. Final thyroxine requirements may not be evident in the initial phase of treatment and patients with apparently low maintenance thyroxine requirements require long-term follow up.

Estimates of normal binding of a human recombinant alpha interferon to peripheral blood mononuclear cells from a study matching healthy subjects to subjects with insulin dependent diabetes.

This study compares the binding of a human recombinant alpha-interferon to peripheral blood mononuclear cells (PBMC) from patients with insulin dependent diabetes (IDDM) mellitus and control subjects. Diurnal and longer term of variation, feeding, fasting and haemoglobin glycosylation were examinated for their influence on interferon binding to PBMC. No gross differences in binding were demonstrated, in particular no effect of glucose levels was seen on the binding of interferon alpha-2 to PBMC.

2'-5' oligoadenylate synthetase and its relationship to HLA and genetic markers of insulin-dependent diabetes mellitus.

Cytokines and their related enzyme pathways may play a part in the development of insulin-dependent diabetes mellitus (IDDM). We have therefore studied the activity of the enzyme 2'-5' oligoadenylate synthetase (which is induced by both interferon and the tumour necrosis factors) in circulating mononuclear cells from 40 subjects with IDDM and 32 healthy control subjects. There was no difference in mean basal enzyme activity between the two groups. A polymorphism of the 2'-5' oligoadenylate synthetase gene, not previously described, was found using the restriction enzyme Bam HI. There was no association of 2'-5' oligoadenylate synthetase genotypes with IDDM, but there was a significant correlation between basal 2'-5' oligoadenylate synthetase activity and 2'-5' oligoadenylate synthetase genotypes. Significantly higher mean basal levels of 2'-5' oligoadenylate synthetase activity were associated with HLA-DQA 4.6 phenotype (determined using the restriction enzyme Taq 1 and a DQA probe) and HLA-DR3 (determined serologically), whereas significantly lower mean levels of enzyme activity were associated with HLA-DQA 5.5 and HLA-DR7, in both IDDM and control subjects. An analysis of variance confirmed that these associations were independent 2'-5' oligoadenylate synthetase genotype. Likewise, a significantly higher mean level of enzyme activity was associated with the heterozygous 1/3 insulin-related genotype in the IDDM subjects only. This study therefore suggests that the possession of certain HLA haplotypes might be associated with differing levels of basal 2'-5' oligoadenylate synthetase activity.

Corticosteroid replacement therapy: twice or thrice daily?

Although glucocorticoid replacement is conventionally administered twice daily, the pharmacokinetics of hydrocortisone would predict very low levels of plasma cortisol by mid-afternoon. This study compared plasma cortisol day profiles in 7 hypoadrenal patients while on twice daily and thrice daily hydrocortisone replacement. The twice daily regimen was associated with very low levels of cortisol at 16.00 and 18.00 h. This was eliminated by administering the same total dose in a thrice daily regimen. Furthermore, estimates of 'well-being' by visual analogue scale correlated significantly with simultaneous plasma cortisol levels and 5 of the patients expressed a preference for the thrice daily regimen. The findings suggest that thrice daily glucocorticoid replacement therapy should be adopted routinely.

The beta-2 microglobulin urine-to-serum ratio: an early marker of renal dysfunction in primary hyperparathyroidism.

Human beta-2 microglobulin (beta-2 M) is released into body fluids as a result of cell turnover, excreted by the kidney, and catabolized in the proximal tubule. Urinary excretion rates constitute a sensitive index of renal tubular function. The beta-2 M urine-to-serum ratio was measured in 25 patients with primary hyperparathyroidism (15 preoperative and 10 treated conservatively) in addition to 20 age- and sex-matched control subjects. The ratio was found to be significantly higher in both the operative and the conservatively managed groups compared to controls (p less than 0.05, Mann-Whitney U test). After surgical excision of a single parathyroid adenoma in the 15 operative cases, the beta-2 M urine-to-serum ratio fell to normal limits. These preliminary findings indicate that the urine-to-serum beta-2 M ratio may be of value in detecting change in renal function in asymptomatic patients with hyperparathyroidism. Further studies are indicated to establish whether these subtle changes are associated with long-term morbidity.

Relationship between retinopathy and glycaemic control in insulin-dependent and non-insulin-dependent diabetes.

The possible relationship between antecedent diabetic control, as determined by serial glycosylated haemoglobin (HbA1) measurements, and diabetic retinopathy was examined in 40 insulin-dependent and 41 non-insulin-dependent diabetics selected consecutively from our clinic population. Multiple logistic regression analysis demonstrated a significant association between mean HbA1 and prevalence of retinopathy in both groups of patients. This association was independent of duration of diabetes which was also significantly associated with retinopathy prevalence. Hypertension and smoking were not obvious risk factors in this group of patients; an apparent association of hypertension and diabetes was entirely accounted for by a positive relationship between the presence of hypertension and duration of diabetes.