Incidental adrenal nodules: association with exaggerated 17-hydroxyprogesterone response to adrenocorticotropic hormone.

The etiology of incidentally discovered, nonfunctional adrenal nodules was evaluated by using the 17-hydroxyprogesterone (17-OHP) response to synthetic adrenocorticotrophin (cosyntropin) (ACTH) administration. Patients who were discovered to have adrenal nodules and age-matched volunteers were studied. A total of 12 patients with adrenal nodules and 10 control subjects were studied. None of the patients with adrenal nodules had any evidence of hormonal hypersecretion consistent with pheochromocytoma, Cushing's syndrome or hyperaldosteronism. All subjects had serum 17-OHP and cortisol responses measured at baseline and at 30 and 60 min following the intravenous administration of 250 micrograms of ACTH. Baseline 17-OHP levels in patients with adrenal nodules were not significantly different from those of the normal controls (adrenal nodules 17-OHP: 75 +/- 13 vs control 68 +/- 11 ng/dl). After stimulation with ACTH, both 30 min and 60 min 17-OHP levels in patients with adrenal nodules (322 +/- 47 and 361 +/- 54 ng/dl, respectively) were significantly elevated over the responses seen with the controls (169 +/- 29 ng/dl at 30 min, p < 0.015, and 158 +/- 20 ng/dl at 60 min, p < 0.004). Baseline and post-ACTH serum cortisol levels were similar in both groups. Out of these twelve patients with adrenal nodules, nine were reevaluated twelve months later. In this group the basal 17-OHP remained comparable to normal levels (72 +/- 8.4 ng/dl) whereas the post-ACTH levels still remained exaggerated (30 and 60 min values 327 +/- 37 and 373 +/- 39 ng/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

New concepts in managing diabetic foot infections.

Recent enhanced attention to diabetic foot infection--in both clinical care and research--has yielded a modified picture of this disorder. It suggests that certain diabetic patients may have important risk factors for the development of infection, and further, infections in these patients may not have the same clinical characteristics as the soft tissue or bony infections found in nondiabetic subjects. Treatment of diabetic patients should therefore be modified to conform to the particular characteristics of their infections.

Pheochromocytoma associated ventricular tachycardia blocked with atenolol.

Ventricular tachycardia in patients with phenochromocytoma is rare. We report a patient with a norepinephrine-secreting extra-adrenal pheochromocytoma who had exercise induced ventricular tachycardia. Prior to diagnosis, the patient was treated with a selective beta 1 blocker, atenolol, which resulted in suppression of the dysrhythmia and amelioration of the hypertension. This is the first reported case of selective beta blockade suppressing ventricular tachycardia in a patient with a pheochromocytoma. Electrocardiographic abnormalities described in patients with pheochromocytoma are reviewed.

Decreased free fraction of thyroid hormones after prolonged Antarctic residence.

We investigated the effects of Antarctic residence (AR) on serum thyroid hormone and cardiovascular responses to a 60-min standard cold air (0 degree C) test (SCAT). Serum total thyroxine (TT4) and serum total triiodothyronine (TT3), free T4 (FT4) and T3 (FT3), thyrotropin (TSH), and percent free fraction of T4 (%FT4) and T3 (%FT3) were measured in normal men (n = 15) before and after each of three SCATs. The SCAT was first carried out in California and then repeated after 24 and 44 wk AR. Mean arterial pressure (MAP) and sublingual oral temperature (Tor) were measured before and during each SCAT. The SCAT did not alter thyroid hormones before or after AR. The %FT4 decreased from 0.0334 +/- 0.0017 to 0.0295 +/- 0.0007% (P less than 0.002) with 44 wk AR but without a significant change in TT4 or FT4 for the same period. The %FT3 also decreased from 0.2812 +/- 0.0128 to 0.2458 +/- 0.0067% (P less than 0.005) after 44 wk AR. FT3 decreased (P less than 0.003) but TT3 and TSH were unchanged with 44 wk AR. The decrease in %FT4 and %FT3 may be theoretically accounted for by a 10% increase in either the capacity or the affinity of the serum binding proteins. The SCAT in California increased MAP and did not change Tor. After 44 wk AR, the SCAT no longer increased MAP but did lower Tor. The shift in the Tor and MAP response to the SCAT is consistent with the associated occurrence of cold adaptation during AR. We describe for the first time a decrease in the free fraction of both serum T3 and T4 present with extended polar residence and independent of a SCAT, further characterizing the recently reported "polar T3 syndrome."

Changes in serum triiodothyronine (T3) kinetics after prolonged Antarctic residence: the polar T3 syndrome.

Humans who live in Antarctica for greater than 5 continuous months demonstrate alterations in the hypothalamic-pituitary-thyroid axis. These changes are characterized by 1) increased pituitary release of TSH in response to iv TRH, 2) increased serum clearance of orally administered T3, and 3) normal serum total, free T4, and unstimulated TSH levels. To clarify the mechanism responsible for these findings, serum kinetic studies of 125I-labeled T4 and T3 were carried out in a group of normal men, first in California, then after 20 and 42 weeks of continuous Antarctic residence. The kinetic parameters were calculated by noncompartmental analysis. The mean T4 residence time (MRT) was not different before and after 42 weeks (5.54 +/- 0.50 and 5.08 +/- 0.43 days). The total T4 volume of distribution (TVd) tended to fall over the same period (4.30 +/- 0.12, 3.56 +/- 0.27 L/m2), but was not significantly different (P = 0.075). In contrast to T4, there was an increase from control values for the T3 MRT from 0.83 +/- 0.03 to 1.10 +/- 0.03 days (P less than 0.002) and a more than doubling of the T3 TVd from 15.55 +/- 0.52 to 47.24 +/- 5.09 L/m2 (P less than 0.002) after 42 wk of Antarctic residence. Energy intake increased approximately 40% throughout the study without a change in body weight. The changes in T3 kinetic parameters may be accounted for by increased extravascular tissue binding. The marked increase in T3 TVd and the small increase in MRT are associated with increased T3 production and clearance and only minor changes in T4 kinetics. This is the first description of a mechanism for the change in thyroid hormone economy occurring with extended residence in Antarctica.

Pituitary and peripheral hormone responses to T3 administration during Antarctic residence.

Very little is known regarding hormonal adaptation in human subjects who are exposed to the extremes of temperature and light that are found in polar latitudes. We have previously reported a 50% elevation in the serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH), a fall in serum total triiodothyronine (T3) and free T3 (fT3), and no change in serum total thyroxine (T4) or free T4 (fT4) after 42 wk of Antarctic cold exposure. To differentiate between central and peripheral mechanisms that may lead to these changes, we report the effect of sequentially increasing oral doses of T3 (Cytomel) on serum T3 and fT3 levels and on the resultant attenuation of the TSH response to TRH in nine men before, during, and after 42 wk residence in Antarctica. Serum T3 values basally and following the administration of 25, 50, and 75 micrograms/day of T3 were lower after 42 wk of cold exposure (151 +/- 4, 160 +/- 8, 189 +/- 10, and 222 +/- 14 ng/dl, respectively, compared with control values of 160 +/- 7, 178 +/- 7, 202 +/- 9, and 251 +/- 19 ng/dl, respectively, P less than 0.05). Likewise, the fT3 values measured after these three increasing T3 doses were also lower after 42 wk of cold exposure. The pituitary response to TRH was attenuated by each T3 regimen (48 +/- 6, 68 +/- 4, and 77 +/- 4% decreases in the control period), and this suppression was not different after 20 and 42 wk of Antarctic residence.(ABSTRACT TRUNCATED AT 250 WORDS)

Iodide administration enhances thyrotrophin responsiveness to thyrotrophin-releasing hormone during fasting: evidence for normal pituitary feedback regulation.

Short-term fasting in humans is associated with diminished delta TSH to TRH. The purposes of the present study were to reassess basal TSH levels and TRH responsiveness during fasting utilizing a sensitive radioimmunoassay (RIA: sensitivity 0.3 microU/ml; normal range 0.66-2.98 microU/ml) and to determine if normal feedback regulation is maintained during the fasting state. Eight control subjects (C) and six iodide-treated (I) subjects (262 mg/d) were studied in the fed state and on day 10 of fasting. T3, T4, and TSH were measured by RIA, and free T4 and free T3 by equilibrium dialysis. Basal serum TSH levels in the control group were 2.0 +/- 0.3 microU/ml (mean +/- SEM) in the fed state and increased to 14.7 +/- 3.5 microU/ml 20 min after TRH administration. The fasting basal TSH level of 1.6 +/- 0.3 microU/ml was significantly decreased (P less than 0.01) compared to control, as was the level of 8.8 +/- 2.3 microU/ml (P less than 0.01) obtained 20 min after TRH. In the iodide-treated group the basal TSH level was 1.4 +/- 0.2 microU/ml during feeding which increased (P less than 0.025) to 2.9 +/- 0.7 microU/ml during fasting; the TSH value 20 min after TRH was 12.6 +/- 2.5 microU/ml while feeding and 17.3 +/- 2.9 microU/ml while fasting. Free and total T3 decreased during fasting in both groups. Total T4 was unchanged between the fed and fasted periods in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in the hypothalamic-pituitary-thyroid axis after prolonged residence in Antarctica.

The human population which lives and works in polar environments has been increasing steadily over the last 15 years. Very little is known about how these residents adjust to their environment. Cold adaptation in man is a poorly understood phenomenon. Euthermic mammals maintain body temperature during cold exposure via non-shivering thermogenesis, a process which is hormonally mediated. We studied prospectively the response of the hypothalamic-pituitary-thyroid axis in 17 euthyroid men before, during and after assignment to duty in the Antarctic. Serum total and free T4 levels fell slightly but not significantly after very prolonged Antarctic residence. Serum total and free T3 decreased significantly from basal levels of 170 +/- 3 ng/dl and 388 +/- 19 pg/dl to 155 +/- 5 ng/dl and 319 +/- 14 pg/dl respectively after Antarctic duty. Serum T3 levels increased after 42 weeks of polar living, the end of the observation period, but the change did not attain statistical significance. The integrated TSH response to TRH administration increased by 50% to 734 +/- 58 microIU.min/ml over warm climate basal response levels of 456 +/- 33 microIU.min/ml by the end of the study. The daily circadian rhythm of serum cortisol was maintained throughout the study period. The alterations in thyroid hormones which we describe, are apparently related to the chronic cold exposure which our subjects experienced in this polar environment.

Decreased phospholipase A2 activity in plasma and liver in uncontrolled diabetes mellitus. A defect in the early steps of prostaglandin synthesis?

Arachidonic acid metabolites and prostaglandins participate in numerous physiologic functions. An enzyme important in the control of prostaglandin production is phospholipase A2. In this study, we have investigated the changes in plasma and hepatic phospholipase A2 activity in diabetes mellitus. In uncontrolled diabetic patients, the postheparin plasma phospholipase A2 level was 18.7 +/- 4.1 U/ml; this value was significantly different from the enzyme activities in control subjects (106 +/- 9.8 U/ml) and in controlled diabetic patients (87 +/- 7.3 U/ml). In the streptozocin-induced diabetic rat model, the postheparin plasma phospholipase A2 level (1.9 +/- 0.45 U/ml) was also decreased when compared with normal (9.4 +/- 1.6 U/ml) and controlled diabetic rats (7.0 +/- 1.3 U/ml). The total hepatic enzyme activity in the uncontrolled diabetic rats was only 21.6% of that seen in control rats. Subcellular fraction studies demonstrated that the enzyme activity is decreased in all fractions in the liver. Liver perfusion studies showed that the heparin-releasable phospholipase A2 activity in the perfusate was significantly decreased in the diabetic rats when compared with control and controlled diabetic animals. We conclude that postheparin plasma and hepatic phospholipase A2 activities are decreased in uncontrolled diabetes mellitus, that the low plasma activity is related to decreased release from the liver, and that the alterations in phospholipase A2 activity in plasma and liver are restored to normal by controlling the diabetic status.

Assessment of calcium homeostasis in the critically ill surgical patient. The diagnostic pitfalls of the McLean-Hastings nomogram.

Hypocalcemia is a common problem in critically ill surgical patients. We prospectively evaluated whether measurement of the total serum calcium (Ca) concentration or calculation of the serum ionized Ca level (by the McLean-Hastings nomogram) accurately reflects the measured serum ionized Ca level. Although 71% and 58% of 156 predominantly surgical intensive care unit (ICU) patients were hypocalcemic by the total serum Ca or calculated ionized Ca level, respectively, only 12% were hypocalcemic by directly measured serum ionized Ca measurement. The total serum Ca and calculated ionized Ca concentrations were sensitive (95% and 89%, respectively) but lacked specificity (32% and 46%, respectively) in predicting ionized hypocalcemia. Analyses of Ca binding to albumin in the serum of surgical ICU patients and normal subjects suggested that there is a circulating factor in critically ill patients that increases the binding of Ca to albumin. These observations may explain why the McLean-Hastings nomogram underestimates the protein-induced changes in serum Ca in critically ill surgical subjects. We conclude that: total serum Ca and calculated ionized Ca concentrations are poor indicators of the true serum ionized Ca status in critically ill surgical patients, and we recommend direct measurement of serum ionized Ca levels in these patients; and variability in the affinity of Ca for binding proteins in critical illness may explain the poor correlation between serum total and ionized Ca measurements.

Enhanced phospholipase A2 activity in rat plasma, liver, and intestinal mucosa following endotoxin treatment: a possible explanation for the protective effect of indomethacin in endotoxic shock.

Endotoxin administration in rats produced a significant increase in plasma, hepatic, and intestinal phospholipase A2 activity within three minutes after injection. The elevated phospholipase A2 activity seen in these tissues returned to normal levels six minutes after injection. The changes in phospholipase A2 activity were dose-dependent within the 0, 10, and 20 mg/kg range of treatment with Escherichia coli endotoxin. This increase in plasma, hepatic, and intestinal phospholipase A2 was abolished by prior treatment of the rats with 3 mg/kg indomethacin, a drug known to improve survival in endotoxic shock. The fact that the change in phospholipase A2 occurs soon after endotoxin administration and that the change in phospholipase is blocked by protective doses of indomethacin suggests that phospholipase A2 activation may be an important initial event in the lethal action of endotoxin, and that the protective effects of indomethacin may be directly related to inhibition of phospholipase A2 activity. Further, in vitro studies of the effects of indomethacin on hepatic phospholipase A2 activity showed that indomethacin significantly inhibited this enzyme. Indomethacin (25 mumol/L) produced 56% inhibition in phospholipase A2 activity and the apparent Ki for indomethacin was 9.2 mumol/L. Kinetic analysis using the Lineweaver-Burk method showed that the indomethacin inhibition was of the noncompetitive type.

Reversible hypocalciuric hypercalcemia associated with hypothyroidism.

Hypothyroidism is known to affect calcium homeostasis by decreasing bone turnover and serum calcium level, and by increasing parathyroid hormone and 1,25-dihydroxyvitamin D concentrations. A 52-year-old hypothyroid woman is described who had hypercalcemia associated with elevated parathyroid hormone and 1,25-dihydroxyvitamin D levels, but decreased 24-hour urinary calcium excretion and ratio of calcium to creatinine clearance. These parameters normalized following thyroid hormone replacement therapy. Hypercalcemia appeared to result from a combination of reduced renal calcium excretion and a change in the "set point" for calcium feedback inhibition of the parathyroid glands. These data suggest that thyroid hormone has a direct effect on the parathyroid glands, regulating parathyroid hormone secretion, and on the kidney's ability to excrete calcium. It is recommended that parathyroid hormone, 1,25-dihydroxyvitamin D, and urinary calcium excretion values be interpreted in light of thyroid hormone status.

Urine glucose testing in the critically ill: a comparison of two enzymatic test strips.

The urine glucose concentration is commonly used to monitor indirectly the degree of hyperglycemia in critically ill patients and to adjust insulin dosage. Most commercially available urine glucose reagent test strips measure the urine glucose concentration from 0% to 2%. When the urine glucose is at the 2% level, the blood glucose concentration may vary over a wide range. We compared a new urine glucose test strip which measures the urine glucose concentration from 0% to 5% versus a conventional strip (0% to 2%) in the analysis of double-voided urine specimens from 285 patients with diabetes mellitus. Both types of test strips were insensitive in detecting hyperglycemia and showed a wide range of blood glucose values for each estimated urine glucose concentration. However, the new test strips which gave measurements at the 3% and 5% urine glucose concentrations allowed for more specificity (99%) in detecting blood glucose levels above 250 mg/dl. We conclude that: (a) test strips measuring from 0% to 5% are superior to conventional 0% to 2% test strips because the 3% and 5% urine glucose readings allow for a high level of specificity in detecting severe hyperglycemia (greater than 250 mg/dl); (b) urine glucose testing is insensitive and nonspecific in detecting hyperglycemia when urine glucose values are 2% or less.

Fasting decreases thyrotropin responsiveness to thyrotropin-releasing hormone: a potential cause of misinterpretation of thyroid function tests in the critically ill.

We have previously reported that caloric deprivation inhibits peripheral T4 metabolism and blunts the TSH response to TRH in euthyroid obese subjects. To determine whether these phenomena also occur in hypothyroid subjects, T4, T3, rT3, and the TSH response to TRH were measured initially and after a 60-h fast in seven hypothyroid patients. Short term fasting caused a 29% decrement in the maximum serum TSH increment and a 32% decrement in the integrated TSH response to TRH (P less than 0.01). In two subjects with mild hypothyroidism, basal TSH as well as the TSH response to TRH were reduced to levels within the normal range. Specifically, basal TSH values decreased from 7.6 to 3.5 microU/ml and from 11 to 4.1 microU/ml. In the seven subjects, mean serum T3 decreased significantly from 88 to 60 ng/dl, (P less than 0.05) and rT3, initially undetectable in six of seven subjects, rose to detectable or low normal values in four of seven subjects, serum T4 remained at 2.7 micrograms/dl during both study periods. We conclude that 1) fasting induces changes in both peripheral thyroid hormone metabolism and the hypothalamic-pituitary axis in hypothyroid individuals which are qualitatively similar to those that occur in euthyroid subjects; and 2) in certain hypothyroid subjects, fasting alone can decrease basal TSH values to within the normal range. If these data can be extrapolated to critically ill subjects whose caloric intake may be diminished, they suggest that basal TSH concentrations in moderately and severely hypothyroid critically ill subjects will accurately reflect the biochemically hypothyroid state. However, mild degrees of hypothyroidism in critically ill subjects might be overlooked due to the lowering effect of fasting or poor caloric intake alone on basal TSH concentrations.

T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model.

Thyroid hormone transport across the blood brain barrier in hypothyroid patients is clinically important yet poorly understood. To study this question, 200 micrograms of thyroxine (T4), 100 micrograms of 3,5,3'-triiodothyronine (T3) and 100 micrograms of 3,3',5'-triiodothyronine (reverse T3) were administered separately to 3 baboons, first iv and at a later date intrathecally (IT). Six animals were used. Three received the iv injections and three received the IT injections. In each of the 18 experiments, cerebrospinal fluid (CSF) and serum specimens were collected serially for 6 h after injection. Mean maximal elevations from baseline in CSF iodothyronine levels were 100 +/- 10 ng/dl after iv T4, 3921 +/- 293 ng/dl after iv T3 and 31 +/- 17 ng/dl after iv reverse T3. When given IT in the same dosages, the mean maximal increases in serum iodothyronine concentrations were: 1670 +/- 600 ng/dl for T4, 806 +/- 405 ng/dl for T3, and 210 +/- 43 ng/dl for reverse T3. In every animal studied, rapid bidirectional transfer of T3 from serum to CSF and CSF to serum occurred, whereas iv T4 resulted in delayed minimal increments in CSF T4 concentration. Isotopic experiments were also performed and the results analyzed using a kinetic model. When 125I-T3 was given iv, the equilibrium point in CSF was observed within 90 min with 1.7% of the administered dose/L able to be counted in CSF at any moment in time. When labeled T4 was given iv, only 0.6% of the administered dose/L was counted in CSF and the equilibrium point was not reached until 360 min. These data suggest: (a) T4, T3, and reverse T3 are all capable of bidirectional transfer across the blood brain barrier, (b) T3 may be a better agent than T4 in treating patients with myxedema coma because T3 crosses more rapidly and more completely from serum to CSF.