Sodium selenite therapy and thyroid-hormone status in cystic fibrosis and congenital hypothyroidism

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Sodium Selenite Therapy and Thyroid- Hormone Status in Cystic Fibrosis

and Congenital Hypothyroidism

E B E R H A R D KAUF, j'' H O R S T DAWCZYNSKI, 2 G E R H A R D JAHREIS , l

EVELYN JANITZKY, ~ AND K LA U S W I N N E F E L D 2

~Childrens Hospital and 2Surgical Clinic o f the Friedrich-Schiller- University, Jena, Germany

Received June 29, 1993; Accepted July 10, 1993

ABSTRACT

The effectiveness of a peroral sodium selenite therapy (115 ~g Se/m 2 BSAJd) administered to cystic fibrosis patients (n = 32) could after three months be identified in a significant serum selenium increase (0.69 --~ 0.96 t~mol/L), a significant malondia ldehyde decrease (2.72 --~ 1.64 t~mol/L), as well as in a significant serum vitamin E increase (4.31 ~ 5.72 ~g/mL). Parallel to that, a serum T~ increase as well as a highly significant decrease in the serum T4lT3-ratio were found, too, which point to improved peripheral "G -* T3 conversion during selenium medication. Type- l - iodothyronine-5 ' -deiodinase has recently been identified as a specific se lenoenzyme.

In the case of congenital hypothyro id ism (n = 37) application of sodium selenite in the above specified dosage yielded a mean serum selenium increase (0.87--~ 1.12 Ixmol/L), a not significant T3 increase (2.57--~ 2.6t nmol/L) as well as a not significant TSH decrease (5.34----* 4.49 mlUFL) wi thout an expected T4 decrease. With the serum lipids, however , a lowering of total cholesterol (4.85 ~ 4.53 mmol/L) simultaneous with a mean increase in HDL-cholesterol (1.52 --~ 1.66 mmol/ L) as welt as a decrease in LDL-chotesterol (2.93 ---* 2.52) could be observed. We view the reduction of the atherogenic serum lipid constellation in the course of selenium medication as an expression of increased thyro id-hormone efficacy.

*Author to whom all correspondence and reprint requests should be addressed.

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248 Kauf et aL

Apart from an improvement of the antioxidant status a stimulation of thyroid-hormone efficacy owing to increased T4 --~ T3 conversion is also noteworthy in sodium selenite medication.

Index Entries: Selenium therapy; thyroid hormones; cystic fibrosis; hypothyroidism.

INTRODUCTION

The present contribution is to point out the fact that apart from the well known and aimed-for influence of sodium selenite therapy on gtu- tathione peroxidase, it is also expected to have effects on thyroid- hormone metabolism as it stabilizes the antioxidant system.

Behne and coworkers (1) have identified Type I-iodothyronine-5'- deiodinase as a selenoenzyme containing one atom of selenium per molecule. This deiodinase is present in the thyroid, liver, and kidneys, and there it causes conversion of thyroxine (T4) into the active thyroid hormone triiodothyronine (T3). That way at least about 85% of T 3 are produced in the organism, only 15% originate directly in the thyroid.

Concluding from the presented facts and interrelations, selenium has to be assessed as one factor influencing thyroid-hormone efficacy (2). We have therefore examined patients undergoing sodium selenite therapy from the point of view of the thyroid-hormone status.

CYSTIC FIBROSIS

These patients suffer from hereditary pathologic viscosity of all exogenic glandular secretion causing recurrent pulmonary infections, chron- ic hypoxia as well as a comprehensive disorder of the enteric nutrient absorption (maldigestion and malabsorption). Although it is true that with those patients lipolysis in the gut is particularly disturbed so that there is a deficit of liposotuble vitamins like vitamins E and A, the occurring steatorrhea, however, also leads to a malabsorption of miner- als, among others a malabsorption of selenium. This in turn causes a massively disturbed antioxidant system. Appropriate preliminary exam- ination of our cystic fibrosis patients and reports in the literature demon- strated the result of low selenium and vitamin E contents in the disease so that the indications for peroral sodium selenite therapy were evident.

MATERIALS AND METHODS

After the parents had been informed about and had consented to the therapy, 32 cystic fibrosis patients aged 13.8 _+ 7.2 yr, 15 female and 17 male, received a three months ' peroral sodium selenite substitution in a dosage of t15 ~xg selenium/m 2 BSA/d. The analysis of selenium was

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Se in CF and Hypothyroidism 249

carried out using AAS 3/HG hydride system Carl Zeiss Jena GmbH and that of alpha-tocopherol using HPLC. The thyroid hormones T 3 and T4, but also the hypophyseal TSH (thyroid stimulating hormone) were deter- mined by radio-immunoassay. The analyses were performed in the plasma from a matutinal fasting blood sample taken prior to and toward the end of the sodium selenite therapy.

RESULTS

Table 1 shows the contents of selenium, vitamin E, malon- d i a l d e h y d e , T3, as well as T 4 in the plasma of cystic fibrosis patients prior to and after three months sodium selenite therapy. From this it is clearly recognizable that the plasma selenium level rises out of the reduced range of 0.69 to 0.96 p, mol/L, that is into the normal. At the same time the plasma vitamin E level increases significantly as well without additional substitution having taken place. The malondialdehyde contents as indi- cators of the disturbed antioxidant system fall from the somewhat high initial value to the normal, whereas the T 3 content slightly increases and along with this the plasma T4FF~-ratio significantly decreases. No significant correlations between selenium and the thyroid hormones could be established. Normal range specifications for the individual parameters are contained in Table 1.

DISCUSSION

The presented cystic fibrosis patients are found to show a combined selenium and vitamin E deficiency. Until now it has generally been estimated that 30% of the patients develop a vitamin E deficiency that especially affects underweight patients. In the case of the Jena cystic fibrosis, 16 out of the 32 patients were underweight, i.e., they revealed a weight deficit of > 10 % of the mean height-related standard weight.

Similarly, the plasma vitamin E content was found to be subnormal in 16 out of 32 patients. The combination of reduced plasma vitamin E and reduced selenium was evident in 13 cases. The effects of sodium selenite treatment observed in our children allow to be interpreted as a lower consumption of vitamin E owing to an improved antioxidative capacity (intensified functioning of se lenium-dependent glutathione peroxidase) combined with the promotion of T4/T3-conversion (selenium stimulation of the 5-deiodinases).

The stated view that selenium has a specific stimulating effect on the iodothyronine-deiodinases is supported by the observed T3 increase and simultaneous decrease in the T4FF3-ratio in the plasma of our patients during selenium substitution. This fact is of importance since it is generally at tempted to achieve a continually anabolic metabolism and age-

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2 5 0 Kauf et at

Table 1 Contents of Selenium, Vitamin E, Malondialdehyde, T 3 as well as T4

in the Plasma of Cystic Fibrosis Patients (n = 32) Prior to and After 3 mo Sodium Selenite Therapy

Prior to After Normal range

Se l~mol/L 0.69 + 0.21 " 0.96 _+ 0.27 1.03 _ 0.20 Vit. E ~,g/mL 4.31 *__ 2.69 b 5.73 _ 3.97 > 4.7 MDA i~mol/L 2.72 _+ 1.43 ~ 1.64 _+ 0.36 1.64 __+ 0.43 T 3 nmol/L 2.14 -*- 0.56 c 2.39 + 0.55 1.2 - 2.80 T4 nmol/L 102.3 + 27.4 ns 98.5 _+ 28.9 58 - 154 T4fF3-ratio 49.8 + 14.2 ~' 43.1 +_ 12.8

Pai red t-test . "p ~ O. 1%. "p < 1%. 'p ~ 5%.

appropr ia te g rowth in cystic fibrosis pat ients by m e a n s of a high-caloric diet.

As the thyro id ho rmones , however , crucially in te rvene in the ene rgy metabol ism and g rowth process, it is significant to opt imize their func- tion in the p resen t se len ium deficit of the cystic fibrosis.

CONGENITAL HYPOTHYROIDISM

Having admin i s t e red se len ium supp lemen ta t i on to chi ldren in an iodine-def ic iency area, Vanderpas et al. (3,6) saw an i m p r o v e m e n t in t h y r o i d - h o r m o n e funct ion in the form of a T3 increase. In the case of hypo thy ro id i sm, that is hypoact iv i ty of the thyroid and r educed "['3 formation. There is also, as a rule, a d is turbance of the lipid metabol ism (4), showing a total cholesterol increase along with a s imul taneous increase in LDL-cholesterol and an increase in the LDL/HDL cholesterol ratio so tha t a l together an a therogenic lipid plasma constellat ion results. As se l en ium deficiencies have been p roved to correlate with the occur- rence of coronary hear t disease (5), a vicious circle regard ing a cardio- vascular risk would have to become apparen t in the case of possibly u n d i a g n o s e d or insufficiently t reated hypo thyreos i s and s imul t aneous se len ium deficiencies.

MATERIALS AND METHODS

Thir ty -seven congeni ta l hypo thy reos i s (age: 9.64 + 5.09 yr; 24 female, 13 male) with regular thyro id h o r m o n e medicat ion (LT4:2.94 - 0.98 ~/kg/d) were tested for the applicability of sod ium selenite (115 ~g Se/m--BSA/d over 3 mo) wi th regard to a possible i m p r o v e m e n t in the


Se in CF and Hypothyroidism 25 l

conversion of exogenically added thyroxine by measuring the thyroid- hormone parameters (T 3, T 4, TSH, all RIAs by Henning) and the plasma lipids (t-chol. enzymatic measuring, CHOD-PAP-method; HDL-chol. enzymatic measuring after precipitation with phosphotungstic acid/ MgCI2; LDL-chol. polyvinyl sulfate precipitation; methods according to Boehringer/Mannheim). With this patient group simultaneous recording of the antioxidant status by determining MDA and vitamin E was not carried out.

RESULTS

"['able 2 shows the results for serum selenium, thvroid hormones, and lipids prior to and after oral sodium selenite therapy. The increase in selenium to 1.12 t~mol/L appeared to be sufficient. However, merely a not significant "['~ increase in the sense of a conversion promotion (from 2.57 to 2.61 nmolFl,) resulted. Similarly, there was also a small and not significant TSH decrease without T 4 decreasing in the same way.

DISCUSSION

The Jena area can be assumed to provide a marginal selenium sup- ply. The normal range for plasma selenium in healthy children is 1.03 + 0.2 i~mol/L, whereas Lombeck et al. D0sseldorf indicate 1.16 lamok[, as the normal for their children. In the case of the hypothyreosis treated by us, we found a mean selenium level of 0.87 I.tmol/L and thus a discretely lowered result that, however, does not yet significantly differ from that of a parallely researched group of healthy children (n = 18, plasma selenium 0.79 +_ 0.21 p.mob'L).

In the course of selenium medication, the thyroid-hormone reaction in the treated hypothyreosis did only vaguely correspond to the expecta- tions, although the T4FI'3-ratio showed a significantly negative correlation with TSH.

The present result is first of all likely to have been influenced by overlapping effects of exogenic [,-thyroxine therapy but possibly also by daily fluctuating resorption conditions of peroral thyroxine. In addition, the selenite dose and the change in plasma selenium might have been too small. However, with the measured serum lipids a clear total cholesterol decrease combined with a simultaneous increase in HDL-cholesterol and a decrease in LDL-cholesterol could be observed during selenium treatment. TSH significantly correlates with LDL-cholesterol. Thus, a reduction of the atherogenic serum lipid constellation had altogether been achieved, which we are inclined to assess as an expression of an intensified thyroid-hormone efficacy during selenite therapy, at least in the hepatocyte.


252 Kauf et aL

Table 2 Selenium, Thyroid-Hormone Parameters (T3, T4, TSH), and Lipid Contents

(Cholesterol, HDL-Cholesterol, LDL-Cholesterol) in the Plasma of Hypothyreosis (n = 37) Prior to and After Three Months'

Sodium Selenite Therapy

Prior to After Normal range

Se ~mol/L 0.87 + 0.16 ~ 1.12 + 0.26 1.03 _ 0.2 T 3 nmol/L 2.58 • 0.48 ns 2.62 + 0.42 1.2 - 2.8 T4 nmol/L 137.5 • 38.7 ns 150.5 _+ 46.7 58 - 154 TSH mIU/L 5.34 • 9.68 ns 4.49 • 9.06 0.2 - 3.5 T4FFB-ratio 31.5 • 44 ~' 53.3 • 29.7 Chol mmol/L 4.86 • 0.98 ~ 4.54 • 0.84 2.8 - 5.0 HDL-chol mmobJL 1.53 • 0.39 b 1.67 • 0.43 0.9 - 1.8 LDL-ehol mmol/L 2.94 • 0.77 b 2.54 m 0.73 1.4 - 3.6 LDL/HDL-ratio 1.99 • 0.63 " 1.61 • 0.66

Paired t-test. )p -< 0.1%. ~p ~ 1%. "p<-- 5%.

SUMMARY AND THESES

Two different pat ient g roups , cystic f ibroses with c o m b i n e d selenium and vitamin E def ic iency and congeni ta l hypo thy reos i s wi th latent se len ium deficit as well as increased s e rum cholesterol and reduced peripheral T4 --~ T3 convers ion , were t reated with s o d i u m selenite pursu ing different objectives. With both g roups an increase in s e r u m se len ium to the lower normal range was achieved. In the cystic fibrosis g roup a direct effect of s o d i u m selenite t rea tment on t h y r o i d - h o r m o n e efficacy could be identified, w h e r e a s in the hypo thy reos i s g roup an indirect effect could be s h o w n .

Conc lud ing from this we pos tu la te the fol lowing theses:

1. Thyro id funct ion dur ing se len ium deficiency is character ized by r educed T 4 - '~ T 3 convers ion .

2. Se lenium subs t i tu t ion boos t s T4 convers ion and leads to a T B increase which , in the overall s cheme of a therapy, e.g. , wi th cystic fibrosis, ough t to be paid a t tent ion to by provid ing a high-caloric diet.

3. Cystic fibrosis pat ients f requent ly s h o w a d i s tu rbed state of the ant ioxidants that first of all requires se len ium the rapy bu t aIso vi tamin E supp l emen ta t i on .

4. In the case of hypo thy reos i s , a poss ib ly existing se l en ium def ic iency shou ld a lways be ru led out. By guaran tee ing a good se len ium s u p p l y status, convers ion of exogenical ly added T 4 into more efficient T3 can be favorably inf luenced in


Se in CF and Hypothyroidism 253

the pat ients . This in t u rn leads to a p lasma choles terol decrease, LDL-reduc t ion as well as an i m p r o v e d LDL/HDL- ratio and therefore resul ts in a r e d u c e d card iovascular risk.

5. Se l en ium s u p p l e m e n t a t i o n genera l ly p r e s u p p o s e s n o r m a l thyro id func t ion and iod ine supp ly . If this is not the case, c o m b i n e d t r e a tmen t o u g h t to be cons idered .

REFERENCES

1. D. Behne, A. Kyriakopolous, H. Meinhold, and J. K6hrle, Acta Endocrinol. 124 Supplo 1, 97 (1991).

2. G. J. Beckett, D. A. MacDougall, F. Nicol, and J. R. Arthur, Biochem. J. 259, 887-892 (1989).

3. B. Contempre, J. E. Dumont, Bebe Ngo, C. H. Thilly, A. T. Diplock, and J. Vanderpas, J. Clin. Endocrinol. Metab. 73, 213-215 (1991).

4. H. Oribe, Nippon Naibunpi Zasshi 65, 781-793 (1989). 5. K. Schmidt and Bayer, W., Vitamine, Mineralstoffe, Spurenelemente 3 Suppl. I,

3-19 (1988). 6. J. Vanderpas, B. Contempre, N. Duale, K. Ntambue, C. H. Thilly, and A. T.

Diplock, Annales d'Endocrinologie 2, 117 (1989).

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Sodium selenite therapy and thyroid-hormone status in cystic fibrosis and congenital hypothyroidism