Dialyzable Fraction Research Articles

Direct and indirect techniques for free thyroxin compared in patients with nonthyroidal illness. I. Effect of free fatty acids.

We examined the effect of endogenous free fatty acids (FFA) on the measurement of free thyroxin (FT4) by five different methodologies represented in 16 different assays in a large number of patients with nonthyroidal illness (NTI). Some, but not all, one-step (analog) FT4 RIAs negatively correlated with FFA concentration. All two-step FT4 RIAs, equilibrium dialysis FT4, and the dialyzable (free) fraction of T4 positively correlated. In contrast, a binding-rate-based FT4 RIA, FT4 indices based on T3 macroaggregated albumin uptake, and T4/TBG ratios did not correlate. We also analyzed the FT4-FFA relationship with a second, more sensitive approach by correlating test results with FFA/albumin molar ratio as an estimate of the "excess" (nonalbumin bound) FFA. We found that all FT4 RIAs, equilibrium dialysis FT4, FT4 indices based on T3 uptake, the dialyzable fraction of labeled T4 in equilibrium dialysis, the fraction of labeled T4 bound to solid phase antibody in the binding-rate-based RIA, and T3 uptake correlated with the FFA/albumin molar ratio. This FFA dependency was comparable among all the various techniques and was relatively small. Thus, increases or decreases in FT4 results due to varying FFA (and albumin) concentrations are highly likely with most currently available methods (only the T4/TBG ratio did not reveal FFA-dependency), but the magnitude of changes varies with the "excess" FFA.

Differential Response of Substance P-Containing Subtypes of Adrenomedullary Cells to Different Stressors*

Adrenal medullary cells produce not only the catecholamines norepinephrine and epinephrine but also a number of peptides; hence, they can be subclassified according to their peptide quality. The present study was an attempt to test whether different stressors address different subclasses of adrenal medullary cells. The adrenal gland of intact male rats was implanted with a dialysis system, and the jugular vein was catheterized. One day after surgery, the adrenal dialysis system was connected to a perfusion pump, and Ringer solution was used for dialysis; dialysate fractions were collected at 15-min intervals, and blood was withdrawn at the end of each fraction period after a 2-h equilibration period. The basal release rates of pituitary PRL and adrenal corticosterone, measured in plasma, and of epinephrine, norepinephrine, and substance P (SP) measured in the adrenal dialysates, were constant during the preshock period. SP concentrations in the blood were below the detection limit of the RIA. Application of mild electric foot shock stress resulted in a marked increase in adrenal catecholamine and SP release. Plasma PRL and corticosterone levels also rose during the time of exposure to foot shock, but plasma SP concentrations remained at undetectable values. In contrast, a metabolic stress i.e. insulin-induced hypoglycemia, did not affect adrenal SP release, although adrenal catecholamine release increased to a larger degree than after foot shock stress. Plasma PRL and corticosterone levels also increased during insulin-induced hypoglycemia. It is concluded that an exogenous stressor (electric foot shock) activates adrenomedullary cells containing catecholamines and SP, whereas these cells are not activated by the stress of insulin-induced hypoglycemia.

Effects of the binding of imipramine to erythrocytes and plasma proteins on its transport through the rat blood-brain barrier.

Brain extraction of a tricyclic antidepressant, imipramine, was investigated using the carotid injection technique in the rat. The extent to which drug binding to plasma proteins and erythrocytes could inhibit the brain extraction was measured. Equilibrium dialysis showed that imipramine is highly bound to human serum albumin (HSA), alpha 1-acid glycoprotein (AAG), lipoproteins, and erythrocytes. The free dialyzable drug fraction was inversely related to the protein concentration. Despite this degree of binding, no significant reduction in the brain extraction of the drug was observed in the presence of HSA, lipoprotein, or erythrocytes. Only AAG reduced the brain transport of this drug in a ratio related to the protein concentration. However, the rat brain extraction was higher than expected from the in vitro measurement of the dialyzable fraction. These data indicate that the amount of circulating imipramine available for penetration in brain exceeds widely the dialyzable fraction of the drug as measured in vitro.

Biotin-dependent expression of the asialoglycoprotein receptor in HepG2.

The asialoglycoprotein receptor (AsGR) is characteristic of fully differentiated hepatocytes. AsGR expression in confluent cultures of HepG2 cells grown in minimal essential medium (MEM) requires a 300-350-dalton dialyzable fraction of fetal bovine serum (FBS). Addition to dialyzed FBS (dFBS) of 10(-7) M biotin or biocytin (Mr 372) permitted full expression of AsGR by HepG2. Affinity chromatography of FBS on streptavidin-Sepharose abolished its ability to support AsGR production. The bound material, when released by heat denaturation and resolved by thin layer chromatography, yielded three cinnamaldehyde-positive components, of which the major detectable one migrates with authentic biocytin and reconstitutes dFBS. Sera from several species, which do not support AsGR production by HepG2, contain less than 10% biotin found in FBS as determined by direct enzyme-linked immunosorbent assay. These results indicate that biotin or a derivative is the low molecular weight serum factor of FBS required for expression of AsGR. Isolation of messenger RNA from HepG2 revealed no difference in AsGR transcripts when cells were grown in MEM-10% FBS or MEM-10% dFBS. Thus a biotin-dependent post-transcriptional event permits the ultimate expression of the AsGR by HepG2 cells.

Alterations in thyroidal economy in a systemic illness induced by turpentine oil injection to the rat.

Injection of turpentine oil (5 microliter/g, sc) to Sprague Dawley rats was associated with a significant reduction in serum concentration of T4, T3 and TSH that lasted throughout 48 h of study. Dialyzable fraction of T4 and resin uptake of T3 did not change for 10 h after turpentine oil injection, but were increased significantly at 24 h and 48 h. Serum rT3 concentration was decreased significantly at 24 h and 48 h. The pituitary content of TSH in the experimental rat was significantly increased at 24 h after turpentine oil injection, but the TSH-beta subunit content was decreased significantly. Serum TSH response to TRH did not change in experimental rats. Thyroidal radioiodine uptake, serum T4, and serum T3 in experimental rats demonstrated little or no increase in response to exogenous bovine TSH. A thyroid hormone binding inhibitor (THBI) was detected in serum and iodothyronine 5'-monodeiodinating activity was decreased significantly in liver, kidney and heart of rats injected repeatedly with turpentine oil. Oxygen consumption of experimental rats did not change appreciably. Our data suggest that administration of turpentine oil to the rat leads, within a few hours of the injection, to a systemic illness associated with marked changes in thyroidal economy.

Effect of leukocyte and other tissue dialysates on NBT reduction and prostaglandin production in mice.

The effects of human leukocyte, porcine spleen and bovine liver dialysate fractions on Listeria resistance were measured by survival studies and by assessing the capacity of peritoneal macrophages to produce superoxide anion (0-2) and prostaglandins. Leukocyte (DLE) and other tissue dialysates were fractionated on a Sephadex G-10 column. Thereafter the significant activities were found in fraction III of DLE, fraction II of porcine spleen and fraction II + III of bovine liver dialysate. The treatment with active porcine spleen dialysate fraction increased the capacity of peritoneal macrophages to generate superoxide anion. On the other hand, this fraction significantly decreased the production of prostaglandin PGE2 and thromboxan B2. These results may indicate that all dialysates can be a source of a non-specifically-acting immunomodulatory preparation and that the infection-resistance-increasing substances seem to operate via the monocyte/macrophage activation.

Effects of low-molecular-weight fractions (LMWF) from milk, egg yolk, and seminal plasma on freezability of bovine spermatozoa

The effects of the dialyzable fractions from bovine seminal plasma, egg yolk, and milk and of two buffer systems (TEST and sodium citrate) on post-thaw sperm motility were studied. Each basic salt solution was used in the experimental design. These solutions were used as extender systems in combination with egg yolk and glycerol. After collection, semen samples were extended (1:20), cooled to 5 °C in 1.5 hr, and frozen in 0.5-cc French straws after 3 hr of equilibration. Post-thaw samples were assayed for percentage of motile cells immediately after thawing and after 4 hr of incubation at room temperature (22 °C). Egg yolk (25%) provided the same protection as did the combination of colloidal material present in the skim milk-yolk extenders. The use of TEST as a buffer provided significantly higher ( P < 0.01) sperm post-thaw motility than milk salts or Na citrate. Sperm survival in extenders containing high concentrations of seminal plasma and/or egg yolk salts was significantly lower ( P < 0.01). Spermatozoa frozen in the presence of 6% glycerol resulted in sperm motility significantly ( P < 0.05) higher than that of spermatozoa frozen with 3% glycerol. However, no difference was observed between these two concentrations when TEST solution was used.

Effect of erythrocytes and plasma protein binding on the transport of progabide and SL 75102 through the rat blood-brain barrier

Brain extraction of two antiepileptic compounds, progabide and its acid metabolite, SL 75102, was investigated using the carotid injection technique in the rat. The extent to which drug binding to plasma proteins could inhibit the brain extraction was measured. Equilibrium dialysis at 4° showed that both drugs were highly bound to human serum proteins, mainly to serum albumin. Progabide is also bound to red blood cells and to lipoproteins. The free dialyzable drug fraction was inversely related to the protein concentration. Similarly, the brain extraction of the drugs in the presence of either albumin, or red blood cells for progabide was inversely related to their respective concentrations. However, the rat brain extraction of both drugs was higher than expected from the in vitro measurement of dialyzable fraction. Furthermore, despite a significant degree of progabide binding to lipoproteins, no significant reduction in the brain extraction of the drug was observed. These data indicate that the amount of circulating progabide or SL 75102 available for penetration in a peripheral tissue such as brain exceeds the dialyzable fraction of drug. However, the in vivo exchangeable drug fraction still parallels the dialyzable fraction, except if the drug is lipoprotein-bound.

Degradative studies of highly proteinaceous Acacia gum exudates

Solutions of the gums from Acacia gerrardii, A. goetzii and A. tumida (percentage N = 1.86, 0.89 and 7.66 respectively) have been subjected to mild acidic hydrolysis; a solution of the gum from A. eriopoda (percentage N = 6.70) has been subjected to ultraviolet irradiation and acidic hydrolysis. Data are presented for the sugar and amino acid compositions of the three products obtained from each gum by the degradative processes used. The results extend those obtained previously for Acacia Senegal gum; acidic hydrolysis and ultraviolet irradiation gave differing yields of the insoluble and dialysate fractions having different analytical parameters. The hydrolysis of A. tumida gum gave a large amount of insoluble proteinaceous material but no dialysate. After mild acidic hydrolysis, rhamnose appeared predominantly in the insoluble proteinaceous fractions from A. gerrardi, A. tumida and A. eriopoda and, in contrast, in the essentially non‐proteinaceous dialysate from A. goetzii gum. As established for Acacia...

Effects of Drug Administration on Gonadotropins, Sex Steroid Hormones and Binding Proteins in Humans

The possible mechanisms by which the administration of drugs may alter the gonadal function in humans are considered in this review. Based on personal data, and on data published in the literature, the following events may occur: (1) blockade of gonadal steroidogenesis; (2) interaction of drug(s) with the steroid-binding protein system in plasma, and (3) interference of drug(s) at the level of the feedback control of gonadotropin secretion. Representative examples of the above mechanisms are as following: (1) Ketoconazole possesses inhibitory effects in vitro on cytochrome P-450. When given in adult males, it decreased the plasma concentrations of testosterone (T) and androstenedione and increased 17 alpha-hydroxyprogesterone levels, suggesting that this drug acts in vivo on gonadal steroidogenesis by blocking the 17,20-lyase. (2) Danazol is a progestagen with high affinity for sex steroid-binding protein (SBP); when given in high dosages in normal males, it increased rapidly the dialyzable fraction (percent protein unbound or free fraction) of T. This suggests that by interacting with the binding sites of SBP, danazol and/or its metabolites displace the fraction of T bound to SBP. However, in males as well as in females, the long-term administration of danazol decreased also the binding capacity of SBP, and consequently increased the free fraction of sex steroid hormones. (3) Dihydrotestosterone (DHT), the most active androgen in many target cells, given at therapeutic dosages to adult males, resulted in a decrease in plasma concentrations of luteinizing hormone (LH) and T, without any significant change in the percent of free T, even though the affinity of DHT for SBP is higher than that of T. This suggests that the main effect of DHT is to inhibit gonadotropin secretion at the central level. (4) Flutamide, a nonsteroidal antiandrogen, increased both LH and T levels, demonstrating its pure antiandrogenic activity on gonadotropin secretion. The consequence(s) of the effects of such drugs on the production, the metabolic clearance rate and the bioavailability of sex steroid hormones are discussed.

The role of thyroxine (T4)-binding serum proteins in oleic acid-induced increase in free T4 in nonthyroidal illnesses.

We studied the effects of various concentrations of oleic acid (0.1-3.3 mM), such as are often found in the serum of patients with nonthyroidal illness, on the dialyzable (free) fraction of T4 (DFT4) in three types of serum samples: pooled normal serum (PNS), pooled pregnancy serum (PPS), and pooled serum of hospitalized patients (PSHP). The samples were extracted with diethyl ether to remove endogenous fatty acids before being tested in the DFT4 assay. Oleic acid caused only a moderate increase in DFT4 in PNS; a significant (greater than 2 SD above control) increase (15%) was found with 2.0 mM oleic acid, and the maximal dose of oleic acid (3.3 mM) caused a 33% increase in DFT4. However, the DFT4-increasing effect of oleic acid was enhanced (increase in DFT4 of 33% caused by 0.9-1.2 mM oleic acid) when the serum tested had low (0.5 times normal) albumin and prealbumin concentrations with either normal (50% PPS) or half-normal TBG (50% PNS). The effect of oleic acid in 100% PSHP was significantly (P less than 0.005) greater than that in 100% PNS, and it was close to that in 50% PNS (increase in DFT4 with 3.3 mM oleic acid, 118% in PSHP vs. 98% in 50% PNS). Normalization of serum albumin in PSHP by adding exogenous albumin markedly reduced the DFT4-increasing effect of oleic acid; the maximal increase in DFT4 of 64% with 3.3 mM oleic acid in albumin-normalized PSHP was equalled with 1.3 mM oleic acid in unmodified PSHP. The data suggest that the serum concentrations of albumin and other T4-binding proteins are important in modulating the DFT4-increasing effect of oleic acid and that oleic acid may contribute to the reduced serum binding of T4 in nonthyroidal illness.

Hormonal Changes in Burned Hamsters

Burned male Syrian hamsters (burn size 23% of body surface) exhibited reduced total (T4) and free (FT4) serum concentrations, a defect in T4 binding to serum proteins manifested by the T4 dialyzable fraction but not the in vitro T3 charcoal uptake, and reduced serum testosterone concentration. These changes are similar to those noted previously in burned humans. Unlike such patients, burned hamsters did not exhibit reduced serum T3 nor elevated rT3 concentrations in a reproducible manner. Pinealectomy performed before burning in hamsters did not prevent the burn-induced depression in serum T4 and testosterone. {Endocrinology 117: 1090–1095,1985)

Serum thyroid hormone binding inhibitor in nonthyroidal illnesses

We have employed the recently developed competitive ligand binding assay (CLBA) to study thyroid hormone binding inhibitor (THBI) in ether extracts of sera of 25 patients admitted to the Medical Intensive Care Unit with a variety of nonthyroidal illnesses (NTI). THBI was detected in 60% ( 15 25 ) of patients using one sample/patient and in 88% ( 15 17 ) using multiple (two to six) samples from different days. Mortality rate and mean serum concentrations of total T 4, total T 3, and albumin were similar in THBI-positive and THBI-negative patients. There was a tendency for a higher frequency of low serum total T 4 in THBI-positive ( 10 15 ) than in THBI-negative ( 3 10 ) patients but the difference was not statistically significant ( P < 0.1 by Chi square). However, the mean dialyzable fraction of T 4 (DFT 4 0.11 ± 0.02%, n = 9 v 0.054 ± 0.004%, n = 10) and DFT 3 (0.54 ± 0.05% v 0.40 ± 0.032%) were both significantly ( P < 0.05) higher in THBI-positive patients than THBI-negative patients. There was a significant correlation between THBI and DFT 4 ( r = 0.55, P < 0.02) or DFT 3 ( r = 0.54, P < 0.02). Prior extraction of serum with ether reduced DFT 4 in NTI patients with high baseline DFT 4 but not in normal subjects or NTI patients with mildly abnormal baseline DFT 4. Addition to a normal serum (0.1 mL) of evaporated ether extract of a pooled NTI serum (0.10- to 3.0-mL equivalent) increased DFT 4 progressively from 0.025% to 0.14%. Similar extract of a pooled serum of normal subjects had little or no effect. THBI caused a 2.1 to 3.7 fold greater increase above baseline in DFT 4 than in DFT 3 of a pooled normal serum. Addition of THBI to a normal serum increased its DFT 4 by 35 to 377% but increased the resin uptake of T 3 (RT 3U) only by 18 to 37%. THBI reduced T 4 binding activity of TBG, albumin or prealbumin in the CLBA. The effect of THBI on T 4 binding activity of TBG was also studied in the competitive protein binding assay of Murphy and Patee. Scatchard plots of the data suggested that THBI reduces T 4 binding to TBG by reducing its affinity for T 4. In the CLBA, THBI activity of ether extract of NTI serum was increased ∼threefold by reducing the amount of albumin from 4.5 mg to 1.5 mg per assay tube. Similarly, THBI was more active when charcoal-treated NTI serum was used in place of charcoal-treated normal serum in the CLBA. The various data suggest that: (1) THBI is present very commonly in sera of NTI patients; (2) THBI inhibits T 4 binding to all three T 4-binding serum proteins; (3) THBI may contribute to high DFT 4, high DFT 3 and the frequently observed discrepancy between DFT 4 and RT 3U in NTI; and (4) Low serum albumin in NTI may enhance the activity of THBI.

Low molecular weight eosinophil chemotactic factor (ECF) in the serum of murine schistosomiasis japonica.

Eosinophil chemotactic activity was detected in the serum obtained at an acute stage of murine schistosomiasis japonica. Gel filtration of the dialyzable fraction of the serum on Sephadex G25 showed that the chemotactic component had an apparent molecular weight of less than 1,000. It was stable to heating, but was sensitive to pronase or carboxypeptidase A digestions, indicating its peptide nature. Eosinophil chemotactic activity of the dialysate of the serum from mast cell-deficient W/Wv mice infected with Schistosoma japonicum was far less than that from normal littermate +/+ mice, although the titers of specific IgE antibody to soluble egg antigen in the serum measured by passive cutaneous anaphylaxis was comparable between them. These results suggest that at least some part of low molecular weight ECF in the circulation seems to be a ECF-A derived from mast cells. Possible biological significance of circulating ECF in schistosomiasis has been discussed.

Effects of aluminum and acid on calcium uptake by the crayfishOrconectes virilis

Aluminum increases in concentration in acidified waters and is sometimes more toxic to aquatic organisms at acidic than at neutral pH. This paper examined the interaction of pH and Al in inhibiting uptake of Ca++ from lake water by postmolt crayfish,Orconectes virilis (Hagen). Aluminum at 200 μg/L in non-acidified media had no effect on45Ca uptake. Media at pH 5.5 without Al reduced45Ca uptake to 30% of that in non-acidified media. Aluminum at each of the concentrations of 200, 500 or 1,000 μg/L in media at pH 5.5 reduced45Ca uptake slightly more, to about 20% of that in non-acidified media. The degree of inhibition of45Ca uptake by Al in acidified media was not related to its concentration. Lack of dose-response may be explained by the limited solubility of Al salts and the limited concentrations of the toxic monomeric species which are present in spite of increases in total Al concentration. These toxic species are presumably in the dialyzable fraction of Al which represented 6 to 17% of total lumogallion-reactive Al in media at pH 5.5 and 1 to 10% of total reactive Al at pH 7.O. At pH 5.5, concentration of dialyzable Al was only 67% higher in 1,000 μg/L than in 200 μg/L Al media. Lack of Al toxicity at pH 7.0 may be explained by changes in Al species to less toxic species and/or the apparent lower solubility of A1C13 in the Precambrian Shield lake water at pH 7.0 than at 5.5. Aluminum toxicity constitutes a small additional stress to moltingO. virilis in softwater lakes acidified to between pH 6.0 and 5.0 which have elevated Al levels. In this pH range, natural populations ofO. virilis subject to acidification fail, apparently because of difficulties of ionic regulation coupled with other factors.

Abnormal thyroid hormone binding to serum proteins in ob/ob and db/db genetically obese mice.

Sera from ob/ob and db/db genetically obese mice exhibited abnormal nonspecific (no antibody present) binding measurements in T4 and T3 RIAs employing dextran-charcoal separations. They also showed decreased charcoal uptake compared to sera of lean controls in a conventional charcoal T4 uptake binding test. After correction for the abnormal nonspecific binding and after extraction of serum, mean serum T4 concentrations were similar in control and ob/ob mice. Mean serum T3 concentrations differed significantly (85 ng/dl in controls and 178 ng/dl in ob/ob) when a correction for altered binding in the T3 assay was made, but not when extracted serum was assayed (109 ng/dl in lean and 124 ng/dl in ob/ob). Dialyzable fractions of T4 and T3 were significantly reduced in both ob/ob and db/db mice. Free T4 concentrations were 0.82 +/- 0.05 (+/- SE) ng/dl in control and 0.61 +/- 0.05 ng/dl in ob/ob sera (P less than 0.01). Polyacrylamide gel electrophoresis showed increased binding of tracer T4 and T3 in ob/ob and db/db sera to a postalbumin with mobility similar to that of human T4-binding globulin. In ob/ob sera, this appeared to result from an increased binding capacity of the postalbumin. After in vivo iv injection of tracer T4 and T3 to ob/ob and lean control mice, analysis of tissue and plasma radioactivity showed that, except for T4 in cerebral cortex, tissue to plasma T4 and T3 ratios were lower in cerebral cortex, cerebellum, and liver of ob/ob mice. In summary, these data show increased binding of T4 and T3 to a postalbumin in two strains of genetically obese mice and, in the ob/ob strain, complex relationships between tissue and serum concentrations of thyroid hormones.

Pineal-induced depression of free thyroxine in Syrian hamsters.

Blind hamsters had no alteration of the dialyzable fraction of serum thyroxine (T4) but had depressed total and free T4 concentrations compared to controls. Prevention of the effects of blinding by pinealectomy indicates pineal influence on circulating free T4 concentration. Parallel changes in free T4 and the free T4 index indicate adequacy of the index in representing pineal-induced changes in free T4.

Reduced serum T4 and T3 and their altered serum binding after burn injury in rats.

Total T4 and T3 concentrations are often suppressed in burned patients. To investigate the significance of such changes, we have characterized serum T4 and T3 after full-thickness scald burns (60% body surface under anesthesia) of 270-gm male Sprague-Dawley rats housed in a light:dark cycle of 14:10 hr. Groups (N = 9-15) of BURN, SHAM (anesthesia, fur clipped, no burn) and CON (controls) were sacrificed on postburn days 8 and 14. T4 and T3 (radioimmunoassay), free indices (FT4I and FT3I = respective total T4 or T3 X in vitro charcoal T3 uptake, T3U), and free concentrations (FT4 and FT3 = total T4 or T3 X respective equilibrium dialyzable fraction, T4DF or T3DF) were not different between CON and SHAM. Compared to SHAM, mean T4 and FT4I (by about 48% of respective SHAM means on both days), TT3 (by 36, 43%), and FT3I (by 38, 45%) (days 8, 14) were suppressed in BURN (all p less than 0.001). T4DF (both days) and T3DF (day 14) were significantly elevated in BURN, demonstrating a deficit in serum binding, but T3U was not. FT4 (by 26, 22%) and FT3 (by 33, 34%) (day 8, 14) were significantly lower in BURN. On either day, covariance analyses (BURN vs. combined CON + SHAM) correlated FT4I or FT3I with respective FT4 or FT3 (all p less than 0.001, slopes not different in BURN vs. CON + SHAM), but the lower FT4I and FT3I in BURN significantly overestimated (all p less than 0.001) the depression of respective FT4 and FT3 in BURN.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Nonthyroidal Illness on Thyroid Function

Despite the absence of thyroid disease, patients with nonthyroidal illness frequently have changes in serum thyroid hormone measurements that may suggest either hypothyroidism or hyperthyroidism. Serum T3 levels are frequently decreased mainly because of a decrease in the rate of T3 production from T4. The free T3 concentration may be either normal or reduced as well. The binding of T4 and T3 by the serum-binding proteins is almost always impaired, resulting in an increase in the dialyzable fraction (free) fraction. This is due to a decrease in the concentration of thyroxine-binding proteins and the presence of circulating inhibitors of binding. If serum T4 concentration remains within the normal range, the free T4 concentration can be increased. However, serum T4 is frequently decreased in patients with chronic and/or severe illness. The decrease in serum T4 in these patients, combined with an increase in the dialyzable fraction, results in normal free T4. In patients who are critically ill, none of the available methods for measurement of free T4 may give results that accurately reflect the euthyroid state. Since T3 is the major active thyroid hormone, it is surprising that patients with decreased serum T3 do not appear hypothyroid. The decrease in serum T3 is probably an adaptive change to nonthyroidal illness, which at least enables the sick patient to conserve protein. The clinical impression of euthyroidism is supported by the finding of a normal serum TSH level in most patients. Although TSH regulation may not be entirely normal in patients with nonthyroidal disease, it is likely that serum TSH will be increased in most sick patients who also have significant thyroid failure. The normal clinical findings in patients with decreased serum T3 may result from an augmentation of those biologic responses associated with the clinical manifestations of the euthyroid state. Several animal models of nonthyroidal disease or starvation show that cells have the ability to modulate some biologic responses to thyroid hormone. Further study should elucidate the mechanisms underlying these changes. This article has emphasized that no single laboratory measurement may reliably predict the thyroid state in patients with nonthyroidal disease. This fact emphasizes the need for careful clinical evaluation of these patients and judicious use of laboratory tests. Because the changes in thyroid hormone metabolism that occur in nonthyroidal disease probably represent adaptive changes to the illness, treatment with L-thyroxine to restore serum thyroid concentrations to the normal range is not indicated.

Hormonal changes in burned hamsters.

Burned male Syrian hamsters (burn size 23% of body surface) exhibited reduced total (T4) and free (FT4) serum concentrations, a defect in T4 binding to serum proteins manifested by the T4 dialyzable fraction but not the in vitro T3 charcoal uptake, and reduced serum testosterone concentration. These changes are similar to those noted previously in burned humans. Unlike such patients, burned hamsters did not exhibit reduced serum T3 nor elevated rT3 concentrations in a reproducible manner. Pinealectomy performed before burning in hamsters did not prevent the burn-induced depression in serum T4 and testosterone.