EFFECT OF SEVERE, CHRONIC ILLNESS ON THYROID FUNCTION

Saturday

EFFECT OF SEVERE, CHRONIC ILLNESS ON THYROID FUNCTION C. J. EASTMAN J. N. CARTER L. LAZARUS J. M. CORCORAN Medical Garvan Institute of Research, St. Vincent’s New South Wales, Australia Hospital, Sydney, Most clinically euthyroid patients with severe, chronic, non-thyroidal illnesses (i.e., " sick euthyroid " patients) have abnormal thyroid-function tests, and consequently assessment of The their thyroidal status may be very difficult. most striking abnormality detected in 75 sick euthyroid patients was a highly significant reduction in the mean total serum-triiodothyronine (T3) levels, with most patients having total T3 levels in the hypothyroid range. The severity of the illness correlated well with the reduction in total serum-T3 levels. The mean absolute free serum-T3 concentration was significantly lower than in the control patients. The mean total serum-thyroxine (T4) levels were also significantly reduced, although, unlike the total serum-T3 levels, they remained within the normal range. The total serum-T4/T3 ratios were generally higher in the sick euthyroid patients compared with the controls. The absolute free serum-T4 concentrations (as measured by the effective-thyroxine-ratio test) were normal, and serum-T.S.H. was not increased in any patient. The mean effective binding capacity of thyroid binding proteins in 11 sick euthyroid patients and the control patients was not significantly different. 3 patients had normal T.S.H. and T3 responses to oral thyrotrophin-releasing hormone (T.R.H.) and 2 other patients had normal T3 responses to intramuscular T.S.H. The major cause of the low total and absolute free serum-T3 concentrations in the sick euthyroid patients seemed to be inhibition of extrathyroidal conversion of T4 to T3. Decreased concentrations of binding proteins are unlikely to contribute greatly to the abnormalities of thyroid-function tests in the patients studied. Depressed production of T.R.H., secondary to stress or undernutrition consequent upon chronic illness, may also contribute by reducing thyroidal hormone output.

Summary

Introduction ABNORMALITIES of in-vitro thyroid-function tests commonly encountered in clinically euthyroid patients with severe, chronic, non-thyroidal illnesses

are

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26 October 1974

(i.e., sick euthyroid patients Reduced serumprotein-bound iodine and total serum-thyroxine levels associated with increased free serum-thyroxine concentrations are well documented in these patients and have been attributed, in the main, to reduced circulating thyroid-hormone-binding protein levels Thus, assessment of thyroid status in patients with chronic debilitating diseases may be very difficult. Radioimmunoassay of triiodothyronine (T3) in peripheral serum has demonstrated the importance of T3 in maintaining euthyroidism and the value of serum-T3 estimations in the assessment of thyroid function.7 Extrathyroidal conversion of T4 to T3 may be an obligatory step in the metabolic action of T4.8 Although the mechanism of, and controlling factors for, conversion of T4 to T3 have not been clearly defined, studies of athyreotic patients on T4replacement therapy have demonstrated a direct correlation between serum T4 and T3 levels, suggesting that T3 production is dependent upon available T4.8,9 Since chronic illnesses produce abnormalities in circulating total and free T4 levels which are not solely attributable to changes in transport proteins,4 this study was undertaken to determine more accurately the thyroidal status of sick euthyroid patients and to clarify the mechanism of the disturbances in thyroid function. Patients and Methods Studies were performed on 75 clinically euthyroid inwith severe, chronic illnesses. There were 57 males and 18 females, aged twenty-one to eighty-four years. They were divided into five groups. Group 1.-25 patients with clinical and biochemical evidence of chronic liver disease (C.L.D.). 7 patients had decompensated C.L.D. manifested by moderate jaundice, ascites, or encephalopathy; the remaining 18 were less severely affected and were described as having com-

patients

pensated C.L.D. Group 2.-18 patients from the intensive-therapy unit with miscellaneous chronic illnesses and acute episodes. Group 3.-15 patients with disseminated malignancy. Group 4.-10 patients with severe chronic obstructive airways disease. Group 5.-7 patients with chronic renal failure maintained on twice-weekly haemodialysis. Serum samples from 37 euthyroid inpatients of similar ages and

with minor illnesses were used as controls. hormone (T.R.H.) tests were performed on 3 patients, and the pituitary and thyroidal responses were determined by serum-thyrotrophin (T.S.H.) and T3 assays on serial blood-samples. A dose of 20 mg. Oral

sex

thyrotrophin-releasing

972 of T.R.H. was administered to each patient, since previous studies in control patients had confirmed the efficacy of this dosage.lo T.S.H. stimulation tests, using 10 units of bovine T.s.H. (’Thytropar’) intramuscularly, were performed in two other patients and the responses determined by serial serum-T3 assays. Total T3,’ total T4,ll and serum-T.s.H.12 concentrations were measured by specific radioimmunoassays. Free T3 concentrations were determined by a modification of the dialysis method of Sterling and Brenner for free T4.13 Free T4 levels were estimated indirectly by measurement of the effective thyroxine ratio (E. T .R. ).14 The effective binding capacity of thyroid binding proteins was measured in sera from 11 representative sick euthyroid patients and 8 control patients by the method of Scatchard as described by Ekins et all Statistical analysis was performed using

Student’st

TABLE II-MEAN

FREE SERUM-T3 CONCENTRATIONS K SICK EUTHYROID PATIENTS

(±S.E.M.)

test.

Results T3 Concentrations There was a highly significant reduction in the mean serum-total-T3 concentration in each group of patients compared with the control subjects (p
I-TOTAL SERUM T3 AND T4 CONCENTRATIONS IN SICK EUTHYROID PATIENTS

the control subjects (r<0005; table I), but with the of the C.R.F. in patients whom they were at exception the lower limit df normal, the mean levels remained within the normal range. In all groups except the C.R.F. patients, there was a considerable degree of overlap of the total T4 values with the control values. The increased total T4/total T3 ratios in the sick euthyroid patients compared with the normal controls are consistent with the greater reduction in T3 compared with T4 (table ill).

Eflective Thyroxine Ratios E.T.R. tests were performed on 38 patients and the mean value ±s.E.M. was 0-97±0’01, range 088-108. Since the normal range for this laboratory is 0’86-113, these results provide indirect evidence that the absolute free T4 levels in sick euthyroid patients are not reduced. *

p <

0,005.

t

p<

0001.

The severity of the illness correlated well with the depression of the serum-total-T3. In all groups total T3 values overlapped with the controls, except in the decompensated C.L.D. and the C.R.F. groups; the smaller number of patients in these groups may explain this difference. There was no significant difference in values before and after hxmodialysis in the patients with chronic renal failure (P>0-05). With the exception of patients with compensated C.L.D., most patients with chronic illnesses had serum-T3 levels comparable with those previously reported for patients with severe hypothyroidism.7 The mean percentage serum-freeT3 concentration in the sick euthyroid patients was higher than for controls, but the mean absolute serumfree-T3 concentration was markedly lower, both differences being statistically significant (P<0-003; table 11). The free T3 levels in the control patients were comparable with the results reported by Jacobs et a1.16 using a radioimmunoassay of serum dialysates. T4 Concentrations Mean serum-total-T4 concentrations were significantly lower in all groups of patients compared with

T.S.H. Concentrations Serum-T.s.H. levels in the 75 patients studied were below the upper limit of normal of 5 fL units per ml. in this laboratory. Due to the sensitivity of the assay. it was not possible to differentiate between normal and subnormal values, and thus abnormally low values could not be excluded in many patients.

Thyroid Binding Proteins The mean effective binding capacity of thyroid bind. ing proteins in the 11 sick euthyroid patients was 20-3 ±1-1 (S.E.M.) g. T4 per 100 ml., and in the 8 control patients it was 22-6 ±0-9 fLg. T4 per 100 ml, This difference was not statistically significant (P>0-05). T.R.H. and T.S.H. Stimulation Tests In the 3 patients studied, serum T.s.H. and total T3 responses to oral T.R.H. were within normal limic· The mean basal T.S.H. level was 20±0’7 jn units pe: ml. and the mean maximum increment was approximately 14 11 units per ml. The mean basal total T level was 46 ±4-8 ng. per 100 ml. and the mer. maximum increment was 65 ±10ng. per 100 ir The total T3 responses after exogenous T.s.H. we:; also normal, with the mean maximum total T

973

being 158 ±28 ng. per 100 ml. These results indicate that normal responsiveness of the pituitary and thyroid glands to stimulation is retained in sick euthyroid patients.

response

Discussion The serum total T3 and free T3 levels were highly significantly reduced in all groups of sick euthyroid and were comparable with those commonly in patients with hypothyroidism.7.17,18 The of the chronic illness correlated well with the reduction in serum-total-T3, as illustrated by the results in patients with compensated compared with decompensated C.L.D. As expected, the abnormalities in total T4 and free T4 levels in our patients accorded with previous reports of sick euthyroid patients 1-’ However, the indirect measurements of free T4 levels by the E.T.R. test did not confirm the pronounced increases that are well documented in some of these patients by direct measurement of free T4 in serum dialysates 1-4 Nevertheless, no individual E.T.R. value was below the normal range. To date, there have been few reports of serum-T3 levels in chronically ill euthyroid patients. Burke and Eastman’ noted the occurrence of subnormal serumT3 levels in euthyroid patients with anorexia nervosa and severe general illness. Sullivan et all9 found markedly reduced serum-total T3 levels in each of 6 patients with severe chronic illnesses and Bivens et a1.20 detected decreased serum-total-T3, increased absolute free T4, and normal serum-T.s.H. levels in a severely ill patient with a carcinoid tumour (increased serotonin levels were not regarded as the cause of the abnormal thyroid-function tests). Ramirez et a1.,21 however, reported normal serum-total-T3 levels in 53 patients with chronic renal failure on haemodialysis, and McConnon et a122 reported normal serum-totalT3 and raised absolute serum-free-T3 levels in 5 patients with " severe hepatic cirrhosis with ascites ". These latter results are difficult to reconcile with our findings. However, Ramirez used a radioimmunoassay technique which tended to overestimate serumT3 levels due to the lack of inhibition of binding proteins in the assay system, and McConnon used a competitive-protein-binding technique which is now believed to overestimate the serum-T3 values. We used a specific, sensitive, radioimmunoassay. Since only the unbound or free fraction of circulating thyroid hormone is regarded as the active portion,23 the combination of decreased absolute serum-free-T3 and increased absolute serum-free-T4 concentrations raises the question of what is the true metabolic status of these patients. There seem to be two possibilities. Firstly, if T3 were the sole bioactive thyroid hormone, with T4 functioning logically a as purely prohormone, our results suggest that sick euthyroid patients are hypothyroid. Since clinical signs of hypothyroidism are seen only after prolonged depletion of tissue hormone levels, our patients may not have had depressed levels for_long enough for the characteristic features to develop, thus accounting for the clinical assessment of euthyroidism. Despite this, a degree of biochemical hypothyroidism may conceivably aid the response to severe illness by decreasing

patients, reported severity

the overall

metabolic-rate,

thus

allowing relatively

energy to be expended for the defence reaction. Although tissue levels of thyroid hormone more accurately reflect thyroid status, there is a direct relationship between the tissue and free serum concentrations. Sullivan et aU9 confirmed that levels of T3 in kidney and liver tissue obtained at necropsy from 6 patients who died after severe, prolonged illnesses were markedly depressed, whereas T4 levels were increased; the corresponding absolute serum-free-T4 levels were more

increased and the serum-total-T3 levels were decreased. Secondly, if T4 as well as T3 has intrinsic biological activity, the increase in free T4 levels may be compensatory in an attempt to maintain a euthyroid state in the presence of decreased free T3 levels. Consequently, the correct assessment of the thyroid status of sick euthyroid patients must await the clarification of the respective physiological roles of the two thyroid hormones. Nevertheless, elevated serum-T.s.H. levels associated with low serum-total-T4 levels not attributable to low binding proteins would identify patients with unequivocal primary hypothyroidism. As can be seen from the total T4/total T3 ratios (table 111), the reduction in total T3 concentrations is much greater than the reduction in total T4 concentrations in sick euthyroid patients. Since the major source- of T3 is peripheral conversion of T4, and because the degree of conversion of T4 to T3 varies directly with the serum-total-T4 concentration (at least in athyreotic patients on replacement therapy), the striking abnormality in serum-total-T3 concentration in our patients seems to be due primarily to a defect in monodeiodination of T4. Whether this is due to the presence of a circulating inhibitor or to decreased activity of the converting enzyme will not be known until the mechanism of the conversion reaction is more fully elucidated. Nevertheless, analysis of the treatment charts of all the patients studied revealed no common drugs or groups of drugs that could be implicated. The increase in the serumfree-T4 concentration could consequently be interpreted as the result of a decrease in monodeiodination -similar to the increase in precursor compoundsassociated with enzyme blocks seen in many other conditions. An abnormality of T4 conversion cannot account for all the disturbances of thyroid function, and decreased serum levels of binding proteins undoubtedly contribute to the reduction in the concentrations of the circulating thyroid hormones in many patients. Significant alterations in the maximal binding capacity of thyroxine-binding prealbumin and, to a lesser extent, thyroxine-binding globulin are well documented in chronically ill patients 1-4 Nevertheless, binding capacity is unlikely to have greatly affected our patients since measurement of the effective binding capacity of thyroid binding proteins was not significantly different from the normal control group. Hormone output from the thyroid gland may be impaired in sick euthyroid patients, although a gross abnormality is unlikely in view of the normal thyroidal response to exogenous and endogenous T.s.H. stimulation. Similarly, a primary pituitary defect causing decreased T.S.H. output is unlikely as the response to administered T.R.H. was normal. However, pituitary T.S.H. output may be suppressed, leading to a decrease

974

GLUCAGON CONTROL OF FASTING

thyroidal hormone output, and there are several possible causes. Firstly, there may be decreased production of T.R.H. Hypothalamic dysfunction is well known in patients with chronic illnesses such as anorexia nervosa and malnutrition, and abnormalities of thyroid function similar to those seen in sick euthyroid patients have been described.24,25 T.R.H. has

in

not not

pituitary T.S.H. output. Although to our knowledge corticotrophin levels have not been measured in sick euthyroid patients, plasma and urinary corticosteroid concentrations in patients with acute medical stress are known to be raised,27 suggesting an increased secretion in response to corticotrophin. Since T.S.H. "

"

secretion is inhibited in the presence of stress-induced

corticotrophin secretion, perhaps at a suprahypophyseal level,28 the adaptation to the acute medical stress in our patients may reduce T.S.H. secretion and lead to reduced hormone output from the thyroid gland. Conclusions Sick euthyroid patients have decreased serum-totalT3 and absolute free T3, low normal serum-total-T4, and normal or decreased serum-T.s.H. concentrations; previous studies have shown that the absolute serumfree-T4 concentrations are normal or increased. Inhibition of extrathyroidal conversion of T4 to T3 seems to be the major cause of the low serum-totalT3 and absolute free T3 concentrations, although decreased concentrations of binding proteins may be a contributory factor. Depressed production of T.R.H., secondary to stress or undernutrition in chronic illness, may also contribute by reducing thyroidal hormone output and producing a state of functional hypothalamic hypothyroidism. Despite the abnormalities of the thyroid-function tests, the definitive assessment of the thyroid status of these patients depends on the clarification of the respective physiological roles of both thyroid hormones. Although the alteration in circulating T3 levels may represent a non-specific consequence of the chronic illness, it may also be a compensatory way of reducing the patient’s metabolic requirements. We thank Mrs C. Batley, Mrs C. Flynn, Sister T. Enright, Miss R. Speilmann, and Miss M. Muir for expert assistance. The work was supported by the National Health and Medical Research Council. Requests for reprints should be addressed to J. N. C.

S. R. BLOOM

F. P. ALFORD

J.

D. N. NABARRO

Middlesex

Hospital, London

W1

R. HALL

been measured in vivo in man because there is a sufficiently sensitive assay, but it seems reason-

able to postulate that its production is decreased in these patients. A similar abnormality is probable in sick euthyroid patients resulting in functional hypothalamic hypothyroidism. Secondly, the elevated serum-free-T4 concentration may exert a negative feedback at the pituitary level. T3 is the major, if not the only, thyroid hormone involved in feedback control of the pituitary-thyroid axis.26 If T3 were the sole regulating hormone, sick euthyroid patients would be expected to have compensatory increases in serum-T.s.H. levels; since this does not occur, the increased serum-free-T4 concentrations may suppress the stimulus to T.S.H. production exerted by the low absolute serum-free-T3 concentration. The stress of severe illness may also contribute to suppression of

’

GLUCOSE IN MAN

Royal Victoria Infirmary, Newcastle

upon

Tyne

G. M. BESSER St. Bartholomew’s

Hospital, London EC1 A.

D. H. COY

J. KASTIN

A. V. SCHALLY Veterans Administration Hospital and Tulane University School of Medicine, New Orleans, U.S.A.

Infusion of growth-hormone release Summary inhibiting hormone (G.H.-R.I.H.) in four and insulin undetectable levels and this was a highly significant decline in plasmaglucose (28±S.E.M. 3 mg. per 100 ml. in 1 hour, p< 001). When plasma-glucagon was maintained by an exogenous infusion, at a level which did not itself significantly alter glucose or insulin concentrations, G.H.-R.I.H. administration resulted in a rise in the mean plasma-glucose (20±10 mg. per 100 ml.). It is concluded that, in man, glucagon plays an important part in the maintenance of fasting plasma-glucose.

fasting subjects reduced plasma glucagon concentrations associated with

to

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1972, 51, 3104. 9. Eastman, C. J., Corcoran, J. M., Lazarus, L., Millar, G. J., Nabarro, J. D. N. Proc. Endocrine Soc. Aust. 1973, 16, 42. 10. Eastman, C. J., Lazarus, L. Horm. Metab. Res. 1972, 4, 58. 11. Corcoran, J. M., Eastman, C. J., Ekins, R. P., Paul, W. J. Endocr 1973, 58, xxii. 12. Raud, H. R., Odell, W. D. Br. J. Hosp. Med. 1969, 2, 1366, 13. Sterling, K., Brenner, M. J. clin. Invest. 1966, 45, 153. 14. Mallinckrodt. Res-o-Mat E.T.R. Diagnostic Test. 15. Ekins, R. P., Williams, E. S., Ellis, S. Clin. Biochem. 1969, 2, 253. 16. Jacobs, H. S., Mackie, D. B., Eastman, C. J., Ellis, S. M., Ekins. R. P., McHardy-Young, S. Lancet, 1973, ii, 236. 17. Larsen, P. R. Metabolism, 1972, 21, 1073. 18. Chopra, I. J., Ho, R. S., Lam, R. J. Lab. clin. Med. 1972, 80, 729. 19. Sullivan, P. R. C., Bollinger, J. A., Reichlin, S. J. clin. Invest 1973, 52, 83a. 20. Bivens, C. H., Marecek, R. L., Feldman, J. M. Am. J. med. Sci. 1973, 266, 427. 21. Ramirez, G., Jubiz, W., Gutch, C. F., Bloomer, H. A., Siegler, R. Kolff, W. J. Ann. intern. Med. 1973, 79, 500. 22. McConnon, J., Row, V. V., Volpe, R. J. clin. Endocr. Metat 1972, 34, 144. 23. Oppenheimer, J. H. New Engl. J. Med. 1968, 278, 1153. 24. Mecklenburg, R. S., Loriaux, D. L., Thompson, R. H., Anderser A. E., Lipsett, M. B. Medicine, Baltimore, 1974, 53, 147. 25. Graham, G. G., Baertl, J. M., Claeyssen, G., Suskind, R., Greenberg, A. H., Thompson, R. G., Blizzard, R. M. J. Pediat. 1973 83, 321. 26. Shenkman, L., Mitsuma, T., Hollander, C. S. J. clin. 1973, 52, 205. 27. Nabarro, J. D. N. Ciba Foundation Study Group no. 27, 1967, p. 28. Koch, B., Jobin, M., Dulac, S., Fortier, C. Can. J. Physiol. Pharma 1972, 50, 360.