Thyroid hormone replacement: an iatrogenic problem.

Thyroid hormone replacement is one of the very few medical treatments devised in the 19th century that still survive. It is safe, very effective and hailed as a major success by patients and clinicians. Currently, it is arguably the most contentious issue in clinical endocrinology. The current controversy and patient disquiet began in the early 1970s, when on theoretical grounds and without proper assessment, the serum thyrotropin (TSH) concentration was adopted as the means of assessing the adequacy of thyroxine replacement. The published literature shows that the serum TSH concentration is a poor indicator of clinical status in patients on thyroxine. The adequacy of thyroxine replacement should be assessed clinically with the serum T3 being measured, when required, to detect over-replacement.

Cardiac troponin I concentrations in people presenting with diabetic ketoacidosis.

BACKGROUND: Elevated troponin concentrations may be observed in a wide spectrum of medical disorders in people without evidence of overt ischaemic heart disease. The prospective relationship between serum cardiac troponin I (cTnI) and diabetic ketoacidosis (DKA) has not been examined in adults. METHODS: Forty patients (14 male and 26 female) with type 1 diabetes were recruited. cTnI, creatine kinase (CK), cystatin C and beta-hydroxybutyrate were measured on admission and at 24, 48 and 72 h post-admission. Daily electrocardiographs were also performed. RESULTS: Four out of forty subjects presenting with DKA had an increase in cTnI (median (SD) 0.06 (0.31) microg/L). One of the subjects had multiple possible reasons for the elevated cTnI concentration. However, the other three subjects had no obvious precipitating factors. This cohort underwent echocardiography and thallium-201 scintigraphy, which revealed no abnormalities. CONCLUSIONS: Minor troponin elevations appear to occur in a small number of subjects with type 1 diabetes presenting with DKA. The clinical relevance of this at this stage remains unknown and further large-scale studies are suggested.

Biological variation of asymmetric dimethylarginine and related arginine metabolites and analytical performance goals for their measurement in human plasma.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase which is believed to be a cause of endothelial dysfunction and has been shown to predict the occurrence of acute coronary events. Data regarding the biological variation of arginine and its methylated derivatives are conspicuously absent from the literature. Such data are important in setting analytical quality specifications, assessing the utility of population reference intervals and assessing the significance of changes in serial results from an individual. MATERIALS AND METHODS: Arginine, homoarginine, ADMA and symmetric dimethylarginine (SDMA) are measured in plasma by high performance liquid chromatography. Twelve healthy volunteers underwent weekly blood sampling for 20 weeks in order to determine the intra- and inter-individual biological variation of these analytes, from which analytical quality specifications, indices of individuality (II) and reference change values (RCV) are derived. Plasma samples from 100 healthy individuals were obtained in order to determine population reference intervals. RESULTS: ADMA and symmetric dimethylarginine (SDMA) exhibit low intra-individual biological variation of 7.4% and 5.8%, respectively, imposing desirable imprecision goals (CV(A)) of < or = 3.7% and 2.9% for these analytes. The described methodology achieves these goals, with analytical CVs of < 3.5% for all analytes. Goals for bias and total error were 3.1-10.1% and 7.2-16.0%, respectively. Reference intervals for ADMA and SDMA were 0.29-0.63 micromol L(-1) and 0.24-0.55 micromol L(-1), but have IIs < 1. RCVs were at least 20% for all analytes studied. CONCLUSIONS: Dimethylarginine concentrations are tightly controlled in health, with the result that imprecision goals for laboratory methods require to be low. Relatively large differences are required between serial results to denote a significant change. Population reference intervals for dimethylarginines are likely to be of limited value in detecting 'abnormality' in an individual from a single result.

Postoperative serum urea is associated with 30-day mortality in patients undergoing emergency abdominal surgery.

BACKGROUND: Emergency abdominal surgery carries considerable postoperative morbidity and mortality. Hypovolaemia is considered to be a cause of renal hypoperfusion, which is associated with a decreased clearance of serum urea and creatinine. This study examines whether the perioperative serum urea and creatinine concentrations are predictors of mortality in patients undergoing emergency abdominal surgery. METHODS: Consecutive patients (n=300) who underwent emergency abdominal surgery were studied. Age- and sex-specific reference intervals were used for the data analysis. Patients with incomplete biochemical (n=51) or mortality data (n=31) or with pre-existing renal failure (n=9) were excluded from the analysis. RESULTS: 209 patients were analysed, of whom 162 (78%) remained alive and 47 (22%) died following surgery. The non-survivors were older (P<0.05), had undergone more extensive surgery (P<0.001) and were more likely to have been admitted to the intensive care unit (P<0.001). The serum urea concentration was higher preoperatively (P<0.05) and on day one postoperatively (P<0.001) in the non-survivors. On multivariate logistic regression analysis, age (odds ratio [OR] 3.27, 95% confidence interval [CI] 1.43-7.47, P<0.005), severity of surgery (OR 2.21, 95% CI 1.14-4.29, P<0.019), admission to intensive care (OR 0.54, 95% CI 0.11-0.54, P<0.001), seniority of anaesthetist (OR 0.50, 95% CI 0.27-0.90, P<0.022) and day one urea (OR 3.33, 95% CI 1.39-7.99, P<0.007) were independently associated with 30-day mortality. CONCLUSIONS: These results indicate that an increased serum urea concentration, but not serum creatinine concentration, in the postoperative period is associated with an increase in 30-day mortality in patients undergoing emergency abdominal surgery.

The glucose response to an oral fat tolerance test in young men with a paternal history of premature myocardial infarction: possible early indication of insulin resistance. The EARS 2 study.

BACKGROUND: Concentrations of cholesterol, triglycerides and glucose are higher in young men with a paternal history of premature myocardial infarction than in age- and sex-matched controls. AIM: To test the hypothesis that insulin resistance constitutes the biological expression of increased coronary risk in these subjects. DESIGN: A total of 407 male university students with a paternal history of premature myocardial infarction (cases) and 415 age- and sex-matched controls were investigated for differences in insulin sensitivity. METHODS: Four methods of assessing insulin sensitivity were used: (i) insulin and glucose responses to an oral glucose tolerance test (OGTT); (ii) insulin and glucose responses to an oral fat tolerance test (OFTT); (iii) minimal modelling of insulin and glucose data from a frequent sample intravenous glucose tolerance test performed on a subset of 55 cases and 50 controls and (iv) homeostasis model assessment (HOMA) of insulin resistance. RESULTS: The OFTT glucose response discriminated between cases and controls, with a smaller fall in glucose in cases compared with controls. The negative area under the glucose curve (AUC) (mean [standard error of the mean (SEM)]) was -1.42 (0.09) mmol min/L in cases and -1.76 (0.09) in controls (P = 0.004). Peak height (mean [SEM]) was -0.65 (0.02) mmol/L in cases and -0.73 (0.02) in controls (P = 0.007). The insulin responses were similar in cases and controls. Insulin AUC (mean [SEM]) was 161 (10) mU min/L in cases and 148 (10) in controls (P = 0.34). This combination of findings suggests that insulin-stimulated glucose uptake was reduced in the cases. These findings were consistent across European regions. None of the other methods revealed any differences between cases and controls. CONCLUSION: In young men with a paternal history of myocardial infarction, an OFTT detects altered insulin sensitivity that is not identified by an OGTT, minimal modelling or HOMA.

The perioperative challenge of nephrogenic diabetes insipidus: a multidisciplinary approach.

Nephrogenic Diabetes Insipidus (NDI) is characterised by the inability of the kidneys to concentrate urine in response to arginine vasopressin (AVP). Such patients typically experience polyuria and polydipsia because of this inability to autoregulate their water balance. This provides a perioperative challenge that could lead to a life-threatening situation. This article documents a patient with NDI who underwent an elective bowel re-anastomosis. Two peak serum sodium values were attained. The first when the patient was retaining sodium due to an inappropriate fluid regimen and the second due to hypovolaemia. The literature is reviewed and principles for NDI perioperative management are proposed.

Lower concentrations of carotenoids in the critically ill patient are related to a systemic inflammatory response and increased lipid peroxidation.

BACKGROUND: Critically-ill patients have low circulating concentrations of vitamin antioxidants. The functional significance of such reductions is not clear. AIMS: To determine whether the presence of a systemic inflammatory response was associated with reduced circulating alpha-tocopherol and carotenoid concentrations and an increase in lipid peroxidation as evidenced by malondialdehyde. METHODS: Healthy controls (n=24) and critically-ill patients (n=43) had circulating concentrations of C-reactive protein, cholesterol, triglycerides, malondialdehyde, alpha-tocopherol, lutein, lycopene, alpha- and beta-carotene measured during ITU stay. RESULTS: In the critically-ill group circulating concentrations of C-reactive protein and malondialdehyde were significantly higher (P<0.05) and cholesterol, triglyceride, alpha-tocopherol, lutein, lycopene, alpha- and beta-carotene were all significantly lower (P<0.01) compared with the control group. In the critically-ill group alpha- and beta-carotene were below detection limits for many patients. After adjusting for cholesterol, lycopene concentrations remained significantly lower (P<0.001) compared with the control group. In the critically-ill patients circulating concentrations of C-reactive protein and malondialdehyde were significantly correlated (r=0.502,P<0.01). CONCLUSIONS: The systemic inflammatory response is associated with increased lipid peroxidation and low carotenoid concentrations indicating that inflammation driven breakdown of carotenoids is an important factor in lowering circulating carotenoid concentrations in the critically-ill patient.

Exercise to exhaustion in the second-wind phase of exercise in a case of McArdle's disease with and without creatine supplementation.

The cardio-pulmonary and biochemical changes observed in a case of McArdle's disease, exercising with increasing work rates to exhaustion in the "second-wind" phase of exercise are reported for the first time. A work rate of 275-325 watts was achieved. Venous blood lactate remained unchanged throughout. The plasma ammonium level reached a plateau of approximately 400 mmol/l at 100 watts. At a work rate of 150-175 watts the ratio of O2 consumption to CO2 production increased, the inverse of an anaerobic threshold. Maximal cardiopulmonary responses were achieved at 200 watts. During the final periods of exercise from 200 to 275/325 watts pulmonary ventilation did not significantly change but there was a decrease in the venous blood H+ concentration, and pO2 and in increase in the pCO2. Creatine supplementation at 25 g/day for five days did not improve exercise performance.

Urinary transferrin, high molecular weight proteinuria and the progression of renal disease.

AIMS: Proteinuria predicts rate of progression in a variety of nephropathies. There is considerable evidence that iron-transferrin is toxic to proximal tubular cells in vitro, and recent clinical work suggests that selectivity of proteinuria influences the outcome of renal disease. The aim of this study was to examine the relationship between the nature of proteinuria and progression of renal disease. METHODS: This was a prospective, cross-sectional study in 66 patients with primary glomerulonephritis, diabetic nephropathy and a variety of other renal diseases. Urinary transferrin was measured by sandwich ELISA and correlated with rate of change in estimated creatinine clearance (ECC). Urinary SDS-PAGE was undertaken to divide proteinuria into tertiles according to molecular weight and to quantify the protein in each tertile. The magnitude of each tertile was then correlated with rate of change in ECC over a median period of 20 months. RESULTS: Rate of change of renal function correlated with total proteinuria (r2 = 18%, p < 0.001) and albuminuria (r2 = 17%, p < 0.001), but not urinary transferrin (r2 = 0%, p = 0.235). On univariate analysis high molecular weight proteinuria (r2 = 21%, p < 0.001), intermediate molecular weight proteinuria (r2 = 15%, p = 0.001) and low molecular weight proteinuria (r2 = 10%, p = 0.005) correlated with rate of change in ECC as did total fasting cholesterol (r2 = 7%, p = 0.003). On multivariate analysis, however, the only independent predictors of rate of change in ECC were high molecular weight proteinuria (r2 = 19%, p < 0.001), and total fasting cholesterol (r2 = 5%, p = 0.035). CONCLUSIONS: We found no evidence to support the hypothesis that iron-transferrin is important in the development of human renal injury. High molecular weight proteinuria correlates more strongly with rate of progression of renal disease than intermediate molecular weight, low molecular weight or even total proteinuria. This suggests either, that one or more high molecular weightproteins are implicated in causing progressive renal impairment, or that loss of size selectivity at the glomerular basement membrane is associated with accelerated tubulointerstitial damage.

The TNF alpha/G-308A polymorphism influences insulin sensitivity in offspring of patients with coronary heart disease: the European Atherosclerosis Research Study II.

There is accumulating evidence for a role of tumor necrosis factor-alpha (TNF-alpha) in insulin resistance induced by obesity. The purpose of this study was to investigate whether the TNF alpha/G-308A polymorphism was associated with responses to oral glucose and fat tolerance tests in a case--control study comparing male offspring with a paternal history of premature myocardial infarction (cases, n=335) to age-matched controls (n=340) recruited from 14 European university populations. Genotype frequencies did not significantly differ between cases and controls. Among cases, those carrying the A allele exhibited a higher area under the curve for insulin (64.5 vs 55.9 mU h/l, P=0.009), a higher increment between baseline concentration and peak of insulin (63.1 vs 52.8 mU/l, P=0.005) and a greater decrease between peak and insulin at 120 min (49.1 vs 36.8 mU/l, P=0.003) than those with the GG genotype. No such effect was observed in control subjects. No association was observed with response to a fat tolerance test either in cases or in controls. The present results suggest that the TNF alpha/G-308A polymorphism might interact with other susceptibility factors to coronary heart disease to predispose to insulin resistance, and that the ability of TNF-alpha to induce insulin resistance may extend beyond obesity.