Feasibility of reducing L-thyroxine dose in patients with a suppressed serum TSH.

A total of 748 patients on L-thyroxine with a suppressed serum TSH were requested to reduce their dose and this was achieved in 601 patients. Thyroxine dosage was reduced by 25 or 50 micrograms of L-thyroxine and patients were reviewed six months later. Of all 601 patients, 54.4% remained with a suppressed serum TSH despite dose reduction and in 5.8% an elevated serum TSH resulted. 25 micrograms reductions and 50 micrograms reductions were equally likely to result in an detectable but non-elevated serum TSH (42.8% vs 34.1% ns) but 25 micrograms reductions were less likely to result in an elevated serum TSH (3.8% vs 10.0% p < 0.01). Only 7/601 patients in the study (1.2%) appeared to require a dose of over 150 micrograms. If dose reduction is thought to be necessary for patients with a suppressed serum TSH, we would recommend 50 micrograms reductions if the original dose is 200 micrograms or more, and 25 micrograms reductions if the original dose is 175 micrograms or less.

Hypomagnesaemia and hypocalcaemia in a patient with ovarian carcinoma.

A patient with disseminated ovarian carcinoma presented with symptoms of hypocalcaemia secondary to hypomagnesaemia. The low serum magnesium (0.4 mmol/l) appeared to be due to renal leakage with no evidence of ureteric obstruction or hydronephrosis on intravenous urogram. Parathyroid hormone activity (serum levels and cAMP response) was normal, despite hypomagnesaemia. The patient's complaints resolved after magnesium and calcium supplementation. Hypomagnesaemia of malignancy is a rare but important complication, and is both poorly recognized and understood.

Primary hyperaldosteronism--evaluation of procedures for diagnosis and localization.

We have reviewed the clinical, investigative and pathological findings in 16 patients with primary hyperaldosteronism, 6 with idiopathic adrenal hyperplasia and 10 with an aldosterone-producing adenoma. The ratio of serum aldosterone to plasma renin activity was > 1400 pmol/micrograms/l/h in all patients when measured supine on a normal salt diet, negating the need for salt loading to confirm primary hyperaldosteronism. Postural changes in serum aldosterone confirmed the presence of an aldosterone-producing adenoma in all but one patient when results on normal and high salt intakes were reviewed together. Nevertheless, the need for salt loading for discrimination is questioned, as the combination of postural changes in serum aldosterone on normal salt intake combined with CT confirmed and localized all aldosterone-producing adenomas. Urinary aldosterone measurements were of little value. Localizing procedures consisting of CT and isotopic scanning using 75Se-seleno-methyl-cholesterol proved most useful; adrenal venous sampling yielded less useful information. The latter may be due to the high predominance of patients (8) showing a background of micronodular hyperplasia with a dominant aldosterone-producing tumour. Only three of these patients have remained normotensive and normokalaemic on no medication. The presence of micronodular background suggests the need for life-long monitoring of such patients.

Long term follow-up of treated hyperthyroid and hypothyroid patients.

The objective was to assess the success rate in patients receiving surgery or radioactive iodine for primary hyperthyroidism and the incidence of subsequent hypothyroidism. A long term follow up of patients on L-thyroxine has also been performed from a cohort of patients on the Tayside Thyroid Register. The case series has been followed-up for up to 21 years. 2,038 patients were registered of whom 90.1% were female. 1,045 had had previous hyperthyroidism and 993 had hypothyroidism. Treatment for thyrotoxicosis varied with age, 80.4% of patients under the age of 40 being treated by thyroidectomy and 72.6% of patients over 50 being given the iodine. Overall 9% of patients required medical therapy alone (carbimazole), and this varied little with age. Compared to radioactive iodine, thyroidectomy was more successful (90.2% vs 82.9%, p < 0.01) and had a lower rate of subsequent hypothyroidism (22.0% vs 47.6% at 5 years, p < 0.001). Of patients treated with radioactive iodine, those who were unsuccessful had received a lower dose (mean 354MBq vs 489MBq, p < 0.001). Of patients receiving L-thyroxine (n = 1,180), 58.5% had a suppressed level of thyroid stimulating hormone, 38% had a detectable but not elevated level, and 3.5% had an elevated level (> 4.0 mU/l). Patients with a suppressed level were taking a higher dose of L-thyroxine than those with a detectable level (114.2 +/- 56.9 micrograms vs 100.4 +/- 45.9 micrograms, p < 0.01), but those with an elevated level were prescribed an even higher mean L-thyroxine dose (137.1 +/- 58.8 micrograms)); many were probably poorly compliant.(ABSTRACT TRUNCATED AT 250 WORDS)

Morbidity in patients on L-thyroxine: a comparison of those with a normal TSH to those with a suppressed TSH.

OBJECTIVE: Patients on L-thyroxine with a 'suppressed' TSH (< 0.05 mU/l) were compared to those in whom TSH was detectable but not elevated (0.05-4.0 mU/l), with regard to morbidity data. DESIGN: Biochemical data from Tayside Thyroid Register was matched to hospital admissions data obtained from Health Board Statistics. PATIENTS: The patients were identified from those registered on the computerized Tayside Register. MEASUREMENTS: Serum T4 and TSH assays, clinical assessment scores, and admission records with regard to ischaemic heart disease, overall fractures, fractured neck of femur and breast carcinoma. RESULTS: Over one year, 1180 patients on thyroxine replacement had clinical and biochemical assessment; 59% had a suppressed TSH and 38% 'normal' TSH. Patients with a suppressed TSH exhibited higher median serum thyroxine levels (146 nmol/l, range 77-252 vs 119 nmol/l, 58-224; P < 0.001). Patients under the age of 65 years on L-thyroxine had an increased risk of ischaemic heart disease compared to the general population (female 2.7 vs 0.7%, P < 0.001; male 6.4 vs 1.7%, P < 0.01), but the risk was no different between those with suppressed and normal TSH. There was no increase in risk for overall fracture, fractured neck of femur or breast carcinoma in those on thyroxine with suppressed or normal TSH. CONCLUSION: Patients under the age of 65 years on L-thyroxine had an increased risk of ischaemic heart disease. There was no excess of fractures in patients on L-thyroxine even if the TSH is suppressed.

The acute effects of corticotropin-releasing factor on energy expenditure in lean and obese women.

Corticotropin-releasing factor (CRF) has been implicated in the development of obesity in genetically obese rodents. We have investigated the effect of 100 micrograms of intravenous CRF on energy expenditure in women, comparing the response in obese and lean volunteers. In response to CRF, energy expenditure as measured by indirect calorimetry increased rapidly with a peak response in both groups reached by two minutes with a ten minute post-CRF response averaging 9.0% in the lean and 11.0% in the obese. Subsequently, energy expenditure remained elevated for a longer duration in the lean compared to the obese. Overall, the total 30 min cumulative metabolic rise was similar in the lean and obese. The increments in energy expenditure were associated with elevation of plasma noradrenaline levels, suggesting the possible involvement of the sympathetic nervous system. The adrenocorticotrophic (ACTH) and cortisol responses to CRF were similar in obese and lean. Intravenous administration of CRF therefore acutely increases energy expenditure in both lean and obese healthy subjects.

Re-evaluation of the captopril test for the diagnosis of primary hyperaldosteronism.

OBJECTIVE: We aimed to re-evaluate the captopril test in the diagnosis of primary hyperaldosteronism. DESIGN: Serum aldosterone and plasma renin activity were measured supine prior to and 60, 90, 120 minutes after oral captopril, 25 mg. PATIENTS: We have performed this test in ten patients with primary hyperaldosteronism, two with hypertension and secondary hyperaldosteronism and in ten normokalaemic patients with essential hypertension. MEASUREMENTS: Validity was assessed by mathematical prediction methods. RESULTS: Using a ratio of aldosterone to plasma renin activity greater than or equal to 1400 pmol/l per microgram/ml/h as a predictor of primary hyperaldosteronism, the captopril test had a sensitivity of 100%, a specificity of 83% and a predictive value of 82% with a 60-minute post captopril evaluation being sufficient. Nevertheless, this test was only marginally superior to a careful analysis of the supine values where a similar ratio in the presence of a normal or suppressed plasma renin activity predicted primary hyperaldosteronism with a sensitivity also of 100% but a slightly lower specificity of 75% and predictive value of 77%. CONCLUSION: Application of the captopril test to patients identified as abnormal by screening confirms all cases of primary hyperaldosteronism but false positive or equivocal results, necessitating further investigation, may occur in some patients with essential hypertension.

A case of skin hyperpigmentation due to alpha-MSH hypersecretion.

A case is presented of generalized skin hyperpigmentation due to alpha-MSH hypersecretion from the pituitary that was most marked in the light-exposed areas. The patient also had secondary adrenal dysfunction, peripheral lymphadenopathy, streptococcal glomerulonephritis and malabsorption. Analysis of this patient's alpha-MSH using high-pressure liquid chromatography (HPLC) showed a novel acetylation profile compared to normal individuals and to patients with Cushing's disease and Nelson's syndrome. Glucocorticoid replacement therapy resulted in suppression of alpha-MSH hypersecretion and complete resolution of the illness.

C1q nephropathy: a pediatric clinicopathologic study.

We report on 15 children with proteinuria, at the nephrotic level in the majority of cases, who had no histologic glomerular alterations (eight cases), or focal and segmental glomerular scarring with (three cases) or without (four cases) mesangial proliferation. In all cases, immunofluorescence (IF) microscopy showed prominent mesangial C1q deposits with variable amounts of immunoglobulins. Ultrastructurally, most had conspicuous mesangial electron-dense deposits. Cases with no glomerular histologic alterations were histologically indistinguishable from minimal change disease (MCD), yet they uniformly had an unsatisfactory response to oral prednisone. Thus, the presence of immune deposits with a prominent C1q contribution identifies a group of cases that respond poorly to steroids and that, if light microscopy is considered in isolation, might otherwise be designated MCD.

Potential use of tumour marker CA 15-3 in the staging and prognosis of patients with breast cancer.

The tumour marker CA 15-3 has been assayed in 130 patients with breast cancer and correlated with stage of their disease at presentation. The median value of CA 15-3 (43 kU/l) in 26 patients with stage IV disease was significantly higher than the median for 97 patients classified as stage I or II (17 kU/l). Values were elevated in 18 of 21 (86%) patients with bone metastases at presentation. For the 41 patients with stage I or II disease presenting with levels of CA 15-3 of greater than 20 kU/l, the disease-free interval and survival were significantly less than for 56 patients presenting with levels of less than 20 kU/l. CA 15-3 provides additional information to conventional staging tests for patients presenting with breast cancer and may also have a role as a prognostic indicator. This may be particularly useful in the selection of patients for neoadjuvant therapy.

Anaphylaxis and desensitization to the murine monoclonal antibody used for renal graft rejection.

The murine monoclonal antibody muromonab CD3 is currently used to reverse acute renal graft rejection. We report a case of systemic anaphylaxis during a muromonab CD3 infusion despite pretreatment with systemic antihistamines and corticosteroids. Rapid intravenous desensitization was performed the following day without untoward reactions and daily muromonab CD3 infusions were successful in reversing renal graft rejection. A second rapid desensitization to CD3 was performed 1 month later without any complications. Serum muromonab CD3-specific IgG and IgE antibodies were detected in serum samples obtained after the anaphylactic reaction. The anaphylactic reaction to muromonoab CD3 monoclonal antibody could have been due to allergen-specific antibodies noted in postreaction serum or a cross-reactive antibody to mouse antigens or both. More importantly, this case illustrates that rapid desensitization can be performed successfully without serious complications; therefore, systemic anaphylaxis can develop in susceptible atopic individuals receiving muromonab CD3 monoclonal antibody for renal graft rejection.

Reactive hypoglycaemia in association with disordered islet function and abnormal hepatic glucose-6-phosphatase activity: response to diazoxide.

Severe reactive hypoglycaemia was confirmed in a non-diabetic male patient by a counter-regulatory hormone (GH, cortisol and catecholamine) response to profound hypoglycaemia induced by an intravenous glucose load. There was also evidence of disordered pancreatic islet cell paracrine regulation with hyperinsulinaemia and absent glucagon response to hypoglycaemia. A defect in the patient's hepatic glucose-6-phosphatase enzyme system was documented. Because of severe symptoms, dietary control was insufficient, but the patient responded clinically and biochemically to 18 months of oral diazoxide therapy. He also showed good biochemical response to a single dose (100 micrograms IM) of the somatostatin analogue octreotide.

Membranoproliferative glomerulonephritis associated with sickle cell disease in two siblings.

The cases of two brothers with sickle-cell anemia complicated by the nephrotic syndrome and membranoproliferative glomerulonephritis are presented. The literature related to this infrequent association is reviewed and possible explanations for the occurrence of the latter in two brothers are discussed.

CA72-4: a new tumour marker for gastric cancer.

To date, tumour markers for gastric cancer have proved unreliable. In this study the value of a new serum marker, CA72-4, was compared with the serum activities of carcinoembryonic antigen (CEA) and CA19-9 in a consecutive series of patients with gastric cancer. The results show that the CA72-4 assay is significantly better at separating stage I and II disease from normal controls (P less than 0.01) than CEA (n.s.) or CA19-9 (n.s.). CA72-4 also gave better differentiation between patients with positive and negative nodes (P less than 0.01) and between those who were serosa positive and negative (P less than 0.01). CEA differentiated between patients with positive and negative nodes (P less than 0.05) but CA19-9 could not. CA19-9 and CEA could not discriminate between patients who were serosa positive and negative. In this study, at a specificity of 95 per cent, the sensitivities of CEA, CA19-9 and CA72-4 were 0.25, 0.41 and 0.94 respectively. These preliminary findings indicate that CA72-4 is a reliable tumour marker of disease stage and activity in gastric cancer. Further longitudinal studies are required for full evaluation of its clinical utility.

Effect of verapamil on cephaloridine nephrotoxicity in the rabbit.

Cephaloridine produces proximal tubular necrosis in the rabbit kidney. Calcium channel blockers have ameliorated tissue injury due to toxic and ischemic insults. To determine whether renal damage caused by cephaloridine could be modified by pretreatment with verapamil, groups of rabbits were given cephaloridine, 100 mg/kg sc, 90 min after administration of verapamil, 200 micrograms/kg iv. Histologic scoring of the extent of proximal tubular necrosis 48 h later demonstrated increased necrosis in the group receiving verapamil plus cephaloridine. Verapamil pretreatment increased the concentration of cephaloridine in the renal cortex at 0.5 hr, but did not alter the peak concentration (2 hr after the dose) or cortical concentrations at 1 or 3 hr. Assay of total calcium content in cortical mitochondria 2 hr after cephaloridine showed that verapamil pretreatment abolished the increased accumulation following cephaloridine administration. We conclude that verapamil does not protect renal proximal tubular cells from the toxic effect of cephaloridine, and that verapamil prevents the cephaloridine-induced uptake of calcium by cortical mitochondria.

Acute renal failure due to pyelonephritis.

Acute renal failure developed in a 3-year-old boy with acute pyelonephritis. Renal biopsy showed acute interstitial infiltration of neutrophils and macrophages. There were also glomerulitis and capillary tuft thrombosis. He required peritoneal dialysis, but subsequently recovered renal function. Prompt antimicrobial therapy is crucial to insure a favorable outcome. Pyelonephritis is an unusual cause of acute renal failure in infants and children.

Clinical utility of assays of glycosylated haemoglobin and serum fructosamine compared: use of data on biological variation.

Assessment of the relative clinical usefulness of glycosylated haemoglobin (HbA1) and serum fructosamine is complicated by their markedly different half-lives. They have therefore been compared using a number of indices derived from data on biological variation, as applied in a study of blood glucose control in newly diagnosed diabetic patients. The within-subject (CVI) and between-subject (CVG) variation of fructosamine and HbA1 were assessed in 8 stable diabetic patients. A slightly smaller relative change, or critical difference, is required between serial HbA1 results than between fructosamine results before a significant change can be said to have occurred. The heterogeneity of within-subject variance is also less for HbA1, rendering the critical difference more generally applicable. HbA1 may therefore be more appropriate for long-term monitoring. Monitoring of blood glucose control of a group of 26 newly diagnosed diabetic patients before the commencement of therapy and 1, 2, and 3 months later by serum fructosamine or HbA1 provided very similar information. Fructosamine responds more rapidly with changes of blood glucose control. However, whether this confers any clinical advantage will depend upon the frequency of testing.

Mesangiolytic glomerulopathy in a bone marrow allograft recipient.

A boy with null-cell leukemia received a bone marrow allograft after preparation with chemotherapy and total body irradiation. Cyclosporine A was not administered following transplantation. Renal biopsy performed 6 months after transplantation because of unexplained deterioration of renal function revealed diffuse mesangiolysis and glomerular sclerosis. The significance of this finding is discussed with reference to similar, recently reported cases.