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Poster SPINA EFIM-2 1999
Abstract and Figures
Introduction: Diagnostic evaluation of thyroid function depends on the assessment of contextually determined laboratory markers, whereas the hidden physiological parameters directly influencing the feedback control‘s behaviour are hitherto inaccessible. In order to enable an alternative approach a mathematical model of the information processing structure was tested for its usefulness for diagnostic decisions.
Methods: SPINA (structure parameter inference approach), a technique derived from an empirical cybernetic model of the pituitary thyroid feedback control, is to facilitate the calculation of constant signal transfer parameters in patients from hormone levels determined only once. One of these parameters is GT, the thyroid‘s maximum secretion rate for T4 that can be calculated as
GT = betaT*(DT+[TSH])*(1+K41*[TBG]+K42*[TBPA])*[FT4]/(alphaT*[TSH])
from actual levels of TSH, FT4 and plasma proteins. The dilution factor for FT4 (alphaT), the T4-clearance-exponent (betaT), the TSH-concentration yielding 50 percent of the maximum thyroid response (DT) and the dissociation constants for TBG and TBPA (K41 and K42, respectively) are constant parameters of this equation. In a first evaluation study 116 healthy volunteers where examined by sonographic inspection of the thyroid, determination of TSH and FT4 and consecutive calculation of GT. Subsequent studies were applied to several thyroid disorders as goiter (n=58), toxic adenoma (n=33) and thyroiditis (Graves disease, Hashimoto and de Quervain thyroiditis, n=52 in sum).
Results: For GT a preliminary reference range from 1.41 to 8.67 pmol/s could be determined. Among all examined subjects GT weakly but significantly correlated with the sonographically ascertained thyroid volume (r*r=0.03, p<0.05). Compared with the control group Hashimoto patients showed a reduced GT (p<0.05), whereas in goiter and Graves patients GT was elevated (p<0.05 and p<0.001, respectively). With respect to all covered thyroid disorders GT showed a higher positive predictive value than the determination of TSH, FT4 or FT3 alone.
Conclusion: GT seems to mirror the thyroid‘s function. Therefore, SPINA might contribute to new diagnostic options.
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This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range.
The central role thyroid hormones play for the control of growth, differentiation and metabolic activity requires precise regulation mechanisms as they are materialized by a multiloop feedback system with nonlinear integrating characteristics.
In order to study the effects that the individual signal transfer mechanisms exert on the entire control system we developed a modular extendable cybernetic model. Making use of our simplest model we can describe the changes in TSH level as d[TSH]/dt=VH*[TRH]/((DH+[TRH])*LS*[FT3])-bS*[TSH], where VH is an amplification factor of the pituitary, determining the maximum secretion rate of TSH, DH an attenuating constant, which is responsible for the curve form of the relationship, LS a feedback coefficient and bS a clearance constant for the degradation of TSH. The TSH concentration in the steady state is then [TSH]=aS*VH*[TRH]/(bS*(DH+[TRH])*LS*[FT3]) with aS as saturation constant. In a similar way it follows that [T4]=aT*VT*[TSH]/(bT*(DT+[TSH])). T4 is bound to plasma proteins, especially TBG and TBPA, so that the equifinal level of free T4 is [FT4]=[T4]/(1+K41*[TBG]+K42*[TBPA]) where K41 and K42 are dissociation constants. The deiodation to T3 is a linear process with the amplification factor VD: [T3]=a3*VD*[FT4]/b3. The resulting concentration of free T3 ist then [FT3]=[T3]/(1+K30*[TBG]) with the dissociation constant K30. Simplifying VH*aS/(LS*bS) to K1, VT*aT/(bT*(1+K41*[TBG]+k42*[TBPA])) to K22 and VD*a3/(b3*(1+K30*[TBG]) to K32 we can summarize the equations to a second degree quadratic equation with the two solutions [TSH]1,2=K1*[TRH]/(2*(DH+[TRH])*K32*K22)+,-sqrt((-K1*[TRH]/(DH+[TRH])*K32*K22))^2+4*DT*K1*[TRH]/((DH+[TRH])*K32*K22))/2.
Due to mathematical reasons there is one positive and one negative solution, while the positive one is identical with the level of TSH the feedback system is aiming at in steady state. In similar ways the equifinal levels for FT4 and FT3 can be calculated.
By the integration of further relations, e. g., time constants, this simple model can be stepwise refined to the desired level of complexity. Using a such improved model within a computer simulation shows fading oscillations and a remarkably high grade of stability against external disturbances.
Hospitalized geriatric patients (N = 354) from an iodine-deficient area were screened with sensitive thyrotropin (TSH), free and total thyroxine (FT4, T4) and total triiodothyronine (T3) to determine the occurrence rate of clinical and subclinical thyroid dysfunction. The diagnostic value of the tests was compared to each other and to that of the thyrotropin-releasing-hormone test (TRH-test) in order to find the optimal first line screening test in geriatric patients. Clinical hyperthyroidism was found in 13, subclinical hyperthyroidism in 10, overt hypothyroidism in 6 and subclinical hypothyroidism in 8 cases. 20.6% of the patients were euthyroid but had subnormal TSH response to TRH, as a sign of possible thyroid autonomy. The low occurrence rate of clinical thyroid disorders (4.8%) does not justify the screening of geriatric patients in general, but the high probability of thyroid autonomy makes reasonable the investigation of every geriatric patient before iodine administration. Suppressed basal TSH and high FT4 were found to be both sensitive and specific in diagnosing clinical hyperthyroidism, but the predictive value was insufficient; elevated T4 and T3 are specific, but not sensitive. Basal TSH is sensitive, specific and has a good predictive value in diagnosing euthyroidism, whereas normal T4, FT4 or T3 are not specific enough for euthyroidism. Basal TSH is better as a first line test of thyroid function than FT4. A normal basal TSH confirms euthyroidism by itself. Other tests (TRH test, T4, FT4, T3) are necessary to elucidate the clinical importance of a subnormal or suppressed basal TSH.
To compare the frequency and causes of abnormal thyrotropin (TSH) levels in ambulatory and hospitalized patients and to assess the specificity and sensitivity of suppressed TSH for the diagnosis of hyperthyroidism in these two settings, analysis of thyroid function tests including sensitive TSH measurement was performed on 715 consecutive patients who had a thyroid panel performed in one clinical laboratory. Suppressed TSH (less than 0.3 mU/L) and elevated TSH (greater than 5.5 mU/L) were found in 35 (8.5%) and 28 (6.5%) of the 411 regular ward inpatients. The prevalence of suppressed TSH was significantly higher than that of high TSH among the 267 ambulatory patients (11.6% vs 5.6%, p less than 0.03). A total of 37 severely ill ICU patients had a significantly higher prevalence of both suppressed and elevated TSH (16% and 22% respectively) than regular ward inpatients and ambulatory patients. Hyperthyroidism and exogenous thyroid hormone administration were responsible for suppressed TSH in 65% of ambulatory patients and in 34% of regular ward and ICU patients. In contrast nonthyroidal illness was implicated in 36% of hospitalized patients and in 6% of ambulatory patients. The sensitivity and specificity of suppressed TSH for the diagnosis of hyperthyroidism was 90% and 91% for ambulatory patients and 100% and 91% for hospitalized patients respectively. The predictive value of suppressed TSH for hyperthyroidism was higher in outpatients (26%) than in hospitalized patients (7%). After patients with known causes for suppressed TSH other than thyroid disease had been excluded, the corrected predictive values of suppressed TSH for hyperthyroidism were 57% in outpatients and 21% in hospitalized patients.(ABSTRACT TRUNCATED AT 250 WORDS)
To determine the prevalence of thyroid dysfunction in institutionalised elderly people in Cape Town and to assess the usefulness of an abnormal thyroid-stimulating hormone (TSH) concentration as a screening test in this group.
Cross-sectional survey.
Four old-age homes in Cape Town.
Old-age home residents aged 60 years and over.
Serum concentrations of TSH, free thyroxine and free tri-iodothyronine.
Serum TSH estimations were performed on 658 participants, and were abnormal in 103 (15.6%)-41 (6.2%) being elevated (> 5.0 microU/ml) and 62 (9.4%) being low (> 0.4 microU/ml). There were 3 newly diagnosed cases of hyperthyroidism and 7 of hypothyroidism. Subclinical disease was diagnosed in 40 subjects. The overall prevalence of thyroid dysfunction in this population was 11.2%. In 22 (3.4%) this had previously been recognised, while in 50 (7.8%) the dysfunction was newly diagnosed by the current survey. The positive predictive value of a TSH concentration > 20 microU/ml in predicting hypothyroidism is 67%, while it will predict 100% of cases of subclinical hypothyroidism. A TSH concentration < 0.1 microU/ml will predict 23% of cases of hyperthyroidism, but 81% of cases of subclinical disease.
The prevalence of thyroid dysfunction in institutionalised elderly people in Cape Town is similar to that reported for elderly people in other centres. Thyroid dysfunction had not previously been recognised in approximately two-thirds of the subjects in this study. The serum TSH concentration is a reliable screening test for thyroid dysfunction in the elderly, but is less useful if used to identify biochemical thyroid disease. An elevated TSH concentration is a better predictor of thyroid dysfunction in the elderly than a depressed TSH concentration.