An algorithmic approach to thyroid function testing in a managed care setting. 3-year experience.

An algorithm (directed thyrotropin [TSH], directed thyroid testing algorithm [DRTSH]) for the initial evaluation and monitoring of thyroid function was established in our institution in 1990. The algorithm begins with measurement of TSH by a sensitive immunoassay. If TSH is either < 0.4 mU/L or > 5.5 mU/L, a free thyroid index (T4 x Resin Uptake Ratio (RU)) is automatically performed on the same sample on the same day. In the setting of a large, predominately outpatient, prepaid health care population, the algorithm reduces unnecessary testing and focuses resources on the patients who need it. Three years after its introduction, physician acceptance of this approach is high ( > 90%), test utilization is reduced, test turnaround time is reduced, and significant cost-savings can be demonstrated.

A characterization of hypothalamic-pituitary-adrenal axis function during and after human cardiac arrest.

OBJECTIVE: This study characterizes hypothalamic-pituitary-adrenal axis function during cardiopulmonary arrest and after return of spontaneous circulation. DESIGN: Prospective case series. SETTING: A large urban emergency department and intensive care unit over an 8-month period. PATIENTS: Two hundred five adult patients presenting in cardiopulmonary arrest to an urban emergency department. Three patients known to be taking corticosteroids were excluded from the study. MEASUREMENTS AND MAIN RESULTS: Cortisol concentrations were measured before and after advanced cardiac life support and for five consecutive hours after return of spontaneous circulation. Adrenocorticotropic hormone (ACTH) concentrations were measured before advanced cardiac life support and when the cosyntropin stimulation tests were performed 6 and 24 hrs after the return of spontaneous circulation. The mean initial serum cortisol concentration was 32.0 +/- 33.1 micrograms/dL (882.9 +/- 913.2 nmol/L). Fifty-three percent of patients had cortisol concentrations of < 20 micrograms/dL (< 552 nmol/L) at the end of cardiac arrest. Among 44 patients who achieved return of spontaneous circulation, 98% had initial cortisol concentrations of > 10 micrograms/dL (> 276 nmol/L) and 73% of patients had initial cortisol concentrations of > 20 micrograms/dL (> 552 nmol/L). Mean serum cortisol concentrations increased significantly (p = .0001) from 1 to 6 hrs after return of spontaneous circulation and decreased significantly (p = .03) from 6 to 24 hrs. A serum cortisol concentration of < 30 micrograms/dL (< 828 nmol/L) was associated with a 96% and 100% mortality rate at 6 and 24 hrs, respectively. Mean ACTH concentrations were increased without a significant difference between the initial and 6-hr concentrations. Mean ACTH concentrations decreased between 6 and 24 hrs (p = .06). There were no significant responses to the cosyntropin stimulation at 6 and 24 hrs. CONCLUSIONS: Cortisol concentrations after out-of-hospital cardiac arrest are lower than those concentrations reported in other stress states. There is an association between cortisol concentrations and short-term survival after cardiac arrest. Survivors have a significantly greater increase in serum cortisol concentrations than nonsurvivors during the first 24 hrs. Lower than expected cortisol concentrations for the extreme stress of cardiac arrest may have pathologic significance in the hemodynamic instability seen after return of spontaneous circulation. The etiology of the low cortisol concentrations may be primary adrenal dysfunction.

Microalbuminuria in clinical practice.

Albumin excretion rate measured by new immunoassays and semiquantitative tests is advocated as a means for early detection of diabetic nephropathy. We determined albumin excretion rate in 276 patients. Albumin excretion rate was normal in 66%, within the microalbuminuric range in 27%, and within the macroproteinuric range in 7%. Significant predictors of albumin excretion rate included presence of hypertension and glycosylated hemoglobin level in type I diabetes mellitus, and years since diagnosis in type II diabetes mellitus. A semiquantitative test was deemed to be of limited diagnostic value. We conclude that testing for early diabetic nephropathy in routine clinical practice gives valuable information and that determination by a quantitative immunoassay based on a single 24-hour urine sample is preferable. The optimal frequency of screening and the levels that determine progressive renal disease have yet to be established.

Contemporary approach to thyroid disease emphasizing use of high-sensitivity thyrotropin assays.

Capabilities of new high-sensitivity immunoradiometric assays for thyroid-stimulating hormone (TSH-IRMA) to distinguish among hypothyroid, euthyroid, and hyperthyroid subjects and patient groups with low TSH for nonthyroidal causes suggested an algorithmic approach (directed TSH) to the evaluation of patients with suspected thyroid disease. Utilizing the algorithm, a TSH-IRMA result outside normal limits (0.5 to 5.0 mU/L) generates follow-up tests on the same sample. The interpretation of thyroid function tests (TSH-IRMA, thyroxine, resin uptake, free thyroxine index) and associated studies in the context of different clinical settings is reviewed. The approach is a cost-effective and efficient utilization of laboratory services.

A thyroid testing algorithm: results of a pilot study.

We conducted a pilot study to evaluate an algorithm for thyroid function testing consisting of initial serum thyrotropin values, measured by a sensitive immunoradiometric assay (TSH-IRMA), followed by a computer-directed decision to order further studies. We divided 216 outpatients according to their serum TSH-IRMA values as follows: suppressed (less than 0.1 mU/L, group I); low (0.1 to 0.4 mU/L, group II); normal (0.5 to 5.0 mU/L, group III); and high (greater than 5.0 mU/L, group IV). Thyroxine (T4), resin uptake (RU), and free thyroxine index (FTI) tests on groups I, II, and IV revealed that T4 and RU were normal for most patients in all groups and FTI was normal in 80% of group I, 93.4% of group II, and 93.3% of group IV. All patients in group I were designated hyperthyroid from either an exogenous or endogenous source. All patients in group II were clinically euthyroid except one; 50% were taking either L-thyroxine or propylthiouracil and 50% had no identifiable thyroid disease. Patients in group IV were hypothyroid. Overall, TSH was more effective in detecting both hypothyroidism and hyperthyroidism than either serum T4, RU ratio, or both combined in FTI since results of these measures fell in the normal range for most patients in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effective long-term immunosuppression maintained by low cyclosporine levels in primary cadaveric renal transplant recipients.

Nephrotoxicity and cost are the major problems in the use of cyclosporine (CsA) in renal transplantation. Thus, maintenance of CsA levels at the lower limits of the therapeutic range is desirable. The lowest CsA level effective in preventing rejection while avoiding nephrotoxicity has not been defined. We report on 44 primary cadaveric renal transplant recipients treated with a protocol that involved a progressive reduction in the trough CsA levels. CsA was initiated at an oral dose of 15 mg/kg, and this dose was adjusted to achieve serum trough levels, as measured by radioimmunoassay, of 150-200 ng/ml during the first month, 100-150 ng/ml during the second month, 75-100 ng/ml during the third month, and 50-75 ng/ml thereafter. Patient and graft survival at 18 months were 94% and 83.6%, respectively. The mean daily CsA doses were 6.7 +/- 3.1 mg/kg at 6 months, 5.5 +/- 3.2 mg/kg at 12 months, and 4.7 +/- 2.4 mg/kg at 18 months. Corresponding trough serum CsA levels were 94 +/- 59 ng/ml, 64 +/- 22 ng/ml, and 44 +/- 21 ng/ml at 6, 12, and 18 months, respectively. Mean serum creatinine concentrations were 1.8 +/- 0.6 mg/dl at 6 months, 1.7 +/- 0.5 mg/dl at 12 months, and 1.6 +/- 0.5 mg/dl at 18 months. The mean serum creatinine concentration at 18 months was not significantly different from that of 18 conventionally treated primary cadaveric renal transplant recipients (1.6 +/- 0.5 vs. 1.4 +/- 0.4 mg/dl, P = .31). A total of 67% of patients did not have any rejection episodes under this protocol, while 71% of patients never developed CsA nephrotoxicity. No patient was taken off CsA for progressive nephrotoxicity. We conclude that trough serum CsA levels of 50-75 ng/ml, as measured by radioimmunoassay, are sufficient to maintain effective immunosuppression in the long-term management of primary cadaveric renal transplant recipients. These values are much lower than previously recommended, and this approach ameliorates chronic CsA nephrotoxicity.

Effect on renal function of change from high to moderate protein intake in type I diabetic patients.

The effects on renal function of moderate restriction in protein intake were studied in 14- to 20-yr-old type I diabetic patients who had no clinical renal disease or hypertension; matched normal subjects served as controls. After assessment of protein intake and renal function, studies were conducted at the completion of each of two consecutive dietary periods of 1 wk. Diets containing 3.5 and 1.5 g X kg-1 X day-1 protein were provided during the first and second periods, respectively. Baseline protein intakes were substantial in both controls (1.86 g X kg-1 X day-1) and diabetics (2.17 g X kg-1 X day-1). Baseline creatinine clearance was increased in diabetics (P = .043). At the end of the high-protein intake period, both diabetics and controls showed similar high values of glomerular filtration rate (GFR) and renal plasma flow (RPF). GFR and RPF decreased markedly (P less than .001) and to a similar degree in both groups after normal protein intake. GFR and RPF in diabetics were not higher than in controls at this point, but filtration fraction was increased in diabetics. Albumin excretion rates were similar in both groups and not influenced by renal function changes. GFR and RPF values correlated significantly with the quantity of protein intake, as estimated from the urea nitrogen appearance rate in both groups. The results suggest that the functional response to variations in protein intake is not altered in the diabetic kidney. In addition, increased renal function in diabetics may be related partly to the excessive protein content in commonly prescribed diabetic diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-IgG combined with rate nephelometry for measuring polyethylene glycol-precipitated circulating immune complexes.

Immune complexes from serum were assayed for IgG by a simple rate-nephelometric method after extraction with polyethylene glycol that removes monomeric IgG. A 30-min preincubation of the extracted material in reaction buffer before the anti-IgG is introduced eliminates falsely increased values owing to precipitation that increased baseline light scatter in the reaction buffer. We found good parallelism in the reaction of anti-IgG with the IgG calibrator, aggregated human globulin, or endogenous immune complex. Thus IgG can be used for calibration in place of aggregated human globulin, greatly simplifying the assay. A good correlation was found between the present assay and the C1q-binding test (r = 0.83). The present assay is both sensitive and reproducible. The extraction and assay are straightforward and can be completed in a single morning after an overnight precipitation. The reagents for extraction are easily prepared and inexpensive, and the materials for assay are available in kit form. We believe this approach to be well suited for many clinical laboratories to measure circulating immune complexes.

Anti-IgG binding test to assay circulating IgG-containing immune complexes from polyethylene glycol precipitates.

We describe a simple approach for assaying immune complexes from serum by using anti-IgG as the indicator after a three-step extraction procedure with polyethylene glycol. Analysis of the data indicates that assays of such extracts for immune complexes by absorbance nephelometry, kinetic light scatter, and immunoradiometric techniques correlate well. For 116 samples, results by absorbance nephelometry correlated (r = 0.86) with those by the C1q-binding test. The present assay and the Raji cell test were more sensitive than the C1q-binding test (p less than 0.001) for detecting increased concentrations of immune complexes in 29 samples from patients with immune-complex-type diseases. The basic approach we describe may lend itself to broad applications for use with various immunoassay techniques.

The measurement of human chorionic gonadotropin for pregnancy testing.

PIP: Human chorionic gonadotropin (HCG) has had the widest application among serveral possible endocrine markers for detecting and monitoring early pregnancy because it normally originates only in trophoblastic tissue, it rises exponentially during early pregnancy as a reflection of trophoblast function, and it is detectable with increased sensitivity and specificity by available analytical methods. HCG is composed of 2 non-covalently bound subunits designated alpha and beta; the beta subunit is biologically and immunologically unique to HCG. HCG exhibits extensive homology in the beta subunit to luteinizing hormone (LH), and both LH and HCG bind with equal affinity to identical receptors in vivo. HCG is detectable by radioimmunoassay (RIA) in the nonpregnant state and in the preimplantation phase of pregnancy. Beginning shortly after implantation, approximately 8 days after presumed ovulation, HCG begins to rise rapidly, reaching a peak 8-12 weeks after the last menstrual period, after which it plateaus. Measurement of HCG levels for pregnancy testing has several limitations, including substantial daily variation in HCG levels in individual women, difficulty in interpreting whether a single value is normal for gestational age, and the length of the biological half-life of intact HCG. The urine concentration of HCG parallels but is not identical to the serum concentration. The UCG-slide test is sensitive to 2000 mlU/ml urine and the UCG-tube test is sensitive to 500-1500 mlU/ml of urine. Both are positive 5-12 days after the missed period. However, LH in menopausal women will occasionally give a positive result and certain drugs may interfere. Radioreceptor assays are sensitive to HCG in serum 14 days after conception. The test will detect most pregnancies by the time of expected menses. Serum protein, drugs, and normal LH surges do not significantly interfere. A qualitative radioimmunoassay using antisera directed toward the unique carboxy-terminal end of the beta subunit of HCG may detect pregnancy 7-10 days after conception. The cost and turnaround times of pregnancy tests vary with their sensitivity. Usually a tube test and confirming examination are sufficient. Quantification of HCG may be useful in diagnosing ectopic pregnancy, providing a prognosis in threatened abortion, and following neoplasms.^ieng

A study of endogenous N-cholylglycine distribution among serum proteins using radioimmunoassay.

The amount of N-cholylglycine endogenously associated with the various protein fractions was assessed in serum of patients with hepatobiliary obstruction using a sensitive radioimmunoassay. In contrast to evidence obtained with cholate, the albumin fraction separated by electrophoresis was found to contain only 2.6% of the total N-cholylglycine, while the alpha 2 region had 64% associated with it. The serum beta-lipoprotein isolated by anionic precipitation also contained significant quantities of the conjugated bile acid, the amount in this fraction being greater in the serum of hyperlipidemic subjects. The results suggest that despite accounting for some 63% of the total serum protein, albumin is not the major carrier of endogenous N-cholylglycine in the circulation.

Profiles in altered metabolism I--the organic acids accumulating in acute non-diabetic ketoacidosis associated with alcoholism.

Several organic acids, among them the acidic catabolites of the branched chain amino acids and tyrosine, have been found to be elevated in the sera of non-diabetic patients presenting acute ketoacidosis associated with alcohol abuse. These findings are interpreted in terms of insufficiency of dietary co-factors required for their further catabolism. Butane-2,3-diol is also found frequently elevated in the urine of these patients and suggests interception of hydroxyethyl thiamine pyrophosphate by circulating high levels of acetaldehyde.