The ınfluence of altered thyroıd state on gastroıntestınal motılıty ın rats

Çağla A yh a n , M.D.* / Salah G han dour, M.D.* / Levhi A k ın , M.D.** Ahm et K ara d a ğ , M.D.** / Berrak Ç. Y e ğ e n , M.D.*

* D e p a rm e n t o f P hysiology, S c h o o l o f M e d ic in e , M a rm a ra U n iv e rs ity , Is ta n b u l, Turkey.

** D e p a rtm e n t o f G e n e ra l Surgery, G ü lh a n e M ilita ry M e d ic a l A c a d e m y , Is ta n b u l, Turkey.

ABSTRACT

Objective: Gastrointestinal symptoms frequently

accompany thyroid dysfunction. Previous

reports on the relationship between the thyroid status and the gut have conflicting results regarding gastric emptying and only a few experimental studies on colonic motility are present. This study was therefore designed to

examine further the effects of changing

thyroid hormone status on gastric emptying and to evaluate small intestinal and colonic motility in experimental hypo/hyperthyroidism in the rat.

Methods: Wistar-Albino rats (220-280 g) of both

Results:

and hypothyroid rats compared to control

group.

Conclusion:

K e y W o rd s : Thyroid hormones,

gastrointestinal motility, colon, gastric emptying, rat.

IN TR O DU CTIO N

The gastrointestinal system may become involved in many disorders of the endocrine system. The initial presentation of the thyroid disease may involve gastrointestinal symptoms (1), which have a critical value in the diagnosis and prognosis of the underlying thyroid disease, as the patient may appear otherwise healthy. Most common gastrointestinal symptoms in hyperthyroid patients are diarrhea, malabsorption and steatorrhea, while constipation, obstipation and gas retention are common in hypothyroid patients.

Shafer et al. (2) have hypothesized that abnormal gut motility is the primary cause of the

gastrointestinal manifestations in

hypo/hyperthyroidism. They have demonstrated

(Accepted 21 February, 2000) Marmara Medical Journal 2000;13(2):64-69

shortened gastrointestinal transit time in hyperthyroidism and increased transit time with subsequent iatrogenic hypothyroidism in the same patients. Some clinical reports suggest that neonatal or infantile hypothyroidism may be a

significant cause of functional intestinal

obstruction, which mimics Hirschsprung's

disease (3).

Published reports on the kinetics of gastric emptying in thyroid disease have conflicting results. Some authors have found the gastric emptying of a liquid, semisolid or solid meal to be normal. On the other hand, prolonged gastric emptying time observed in patients with hyperthyroidism was found to be normal when euthyroidism was restored after pharmacological treatment (4). In a case report described by Groskreutz et al., acute gastroparesis was associated with thyrotoxicosis (5), while increased gastric emptying time was found in hyperthyoid rats (6,7).

Most of the previous reports regarding the relationship between the thyroid hormone and the gastointestinal tract are based on clinical observations, and a few experimental studies on colonic motility are present (3). Although alterations of bowel habits are not uncommonly associated with dysfunction of the thyroid gland, and the gastrointestinal symptoms are frequently attributed to alterations in gut motility, their exact relationship is poorly understood (8).

This study was therefore designed to examine further the effects of alterations in thyroid status on gastrointestinal motility by evaluating gastric emptying, small intestinal transit and colonic motility in experimental models of hypothyroidism and hyperthyroidism in rats.

M ATERIALS A N D M ETHODS Animals

Wistar-Albino rats (220-280 g) of both sexes were housed in an air-conditioned room at a constant temperature of 22 ± 2 °C with 12:12 h light/dark cycle and fed a standard diet and water ad libitum. Experimental protocol was approved by the Marmara University School of Medicine Animal Care and Use Committee.

Experimental Groups

Rats were randomly treated with either PTU (6-n- propyl-2-thiouracil; 20 mg/kg/day, ip, 2 weeks; hypothyroid group; n=16) or T3 (3',3',5- Triiodo-L- Thyronine, 1 mg/kg/day, ip, 7 days; hypertyroid group; n=16). Drugs were obtained from Sigma Chemicals (St Louis, MO, USA). A third group of rats without any treatment served as the

control group (n=12). Experimental

hypo/hyperthyroidism in the rats was

documented by measuring serum T3, T4 and TSH after they were decapitated on the 7th or 14th days, following the commencement of several procedures for the determination of daily food intake, gastric emptying, intestinal transit and colonic motility. Serum T3 and T4 uptake were measured by fluorescent polarization and TSH was measured by radioimmunoassay procedures.

Experimental Design

Food intake was evaluated as the intake of preweighed standard chow (gram) per 100 g of body weight (bw) in 24 hours, following a 14-h fasting period. Stool volume (g/day) and the number of fecal pellets (number/day) were measured in 24 hour on the 5th (hyperthyroid group) and 12th (hypothyoid group) days of the treatments.

Gastric emptying of a solid meal was determined following an overnight fasting. The rats were given 15 g of standard laboratory pellet chow and water ad libitum for 3 hours and the food intake was recorded. Then the rats were deprived of food and water for the subsequent 5 hours, at the end of which decapitation was performed to remove the stomach. Stomachs, with their contents, were weighed and opened along the greater curvature from fundus to pylorus to remove the contents. They were washed in warm saline, blotted dry and then the empty stomach weight was recorded. Gastric emptying of a solid nutrient meal was calculated using the formula; Gastric emptying (%) = 1 — [gastric content (g) / food intake in 3 hours (g) ] x 100.

Intestinal motility was measured by the orogastric infusion of 1 ml of the marker, which was prepared by dissolving activated charcoal and gum arabic (12.5 %, from Acacia tree, Sigma Chemical, St Louis, MO, USA) in saline. Thirty

minutes later, the rats were decapitated and the stomach, small intestine, and cecum was dissected and freed from its mesentery, with its contents retained. The intestine was then measured by placing it longitudinally. The total length of the small bowel and the length of the small bowel filled with the back marker was recorded. Intestinal transit was expressed by the fraction of the total length of the small bowel filled with the visually detectable black marker (%).

Statistics

The data were expressed as means ± SE where (n) indicates the number of rats. Student’s t test for paired and unpaired observations was used as appropiate, where p values of less than 0.05 were considered to be significant.

RESULTS

Hyperthyroidism and hypothyroidism were verified by serum T3 and T4 uptake and TSH values. Daily food intake in the hyperthyroid rats (9.43 ± 0.6 g/100 g bw) was not different from control rats (9.4 ± 1.2 g/1 OOg bw), while a significant decrease in food intake was seen in the hypothyroid rats (5.5 ± 0.3 g/1 OOg bw; p<0.001) (Fig 1).

Both the daily stool volume and the number of fecal pellets were significantly higher in the hyperthyroid rats (10.2 ± 0.9 g, p<0.05 and 53.7 ± 4.0, p<0.01; respectively) compared to control rats (6.5 ± 0.4 g and 37.1 ± 2.9) (Fig 2). A similar but a nonsignificant increase in the stool volume was also seen in the hypothyroid rats (9.2 ± 0.9 g), while the number of fecal pellets was significantly reduced (17.8 ± 1.1; p<0.001) in this group.

Hypothyroid rats had a delay in he gastric emptying of a solid meal (39.0 ± 7.6%) compared

to control rats (70.7 ± 3.5 %; p<0.01) (Fig 3), while the gastric emptying rate in the hyperthyroid rats (78.4 ± 4.0 %) was not different from that observed in control animals. Intestinal transit in 30 minutes remained unchanged both in the hyperthyroid (71.8 ± 1.6 %) and hypothyroid rats (74.3 ± 3.5 %) compared to control group (74.5 ± 0.4 %).

DISCUSSION

Hyperthyroidism may be associated with severe dysfunction of the gastrointestinal tract and gastrointestinal symptoms particularly; diarrhea and malabsorption with steatorrhea are well known symptoms in hyperthyroid patients (9). In

contrast, hypothyroid patients frequently

complain of moderate or severe constipation;

F i g . l . : Daily f o o d i n t a k e in t h e co n tro l, h y p e r t h y ro i d a n d h y p o t h y r o id ra ts.

*** p < 0 . 0 0 1 , c o m p a r e d to c o n tr o l g r o u p .

Table I. Effects of PTU a n d T3 t r e a t m e n t s on se ru m T4, T3 u p ta k e a n d TSH.

Serum T4 T3 uptake TSH

(g/dl) (%) ( lU / m l)

Control group (n=12) 4.35 ± 0.54 57.6 ± 7 .4 1.92 ±0.4

PTU treatment (n=16)-hypotyhroid group 1.86 ± 0 .4 5 * 52.4 ± 1 .3 3.71 ± 0 .67 * T3 treatment (n=16)-hyperthyroid group 13.6 ± 2 .4 * 93.4 ± 3 .1 * 0.62 ± 0.59

* p<0.05, compared to control values.

F l g . 3 G a s t r i c e m p t y i n g r a t e a n d intestinal tran si t in th e co ntrol, h y p e r th y ro id a n d hypo th y ro id rats. * * p < 0 .0 1 , c o m p a r e d to co ntrol g r o u p .

b

F i g . 2 . : (a) S t o o l v o l u m e a n d (b) F e c a l o u t p u t in t h e contr ol, h y p e r t h y ro i d a n d h y p o th y ro id ra ts.

* p < 0 . 0 5 , **p<0.01 a n d * ' * p < 0 . 0 0 1 , c o m p a r e d to c o n tro l g ro u p .

rarely, this may be so severe as to cause ileus (10). Although alterations in gut motility and bowel habits are associated with dysfunction of the thyroid gland, it is still unclear which gut region plays the dominant role in the related motor dysfunction. Apart from the esophageal transit time, which takes only a few seconds and is therefore negligible in this aspect, three main components interplay in the net time of passage of

nutrients down to the cecum, namely gastric emptying, intestinal and colonic transit. Taking into account the results of the present study, it seems logical that if orocecal transit time is decreased in hyperthyroidism a rapid colonic motility would account for the phenomenon,

while the hypomotility observed in

hypothyroidism could be attributed to both delayed gastric emptying and slow colonic transit. Similarly, Jonderko et al. (4) have hypothesized that a rapid gastrocecal passage of chyme rather than an increased rate of gastric emptying accounts for hypermotility. Unchanged intestinal transit in the present study may indicate that altered thyroid function affects primarily colon and the stomach, but not the small intestine. In our experimental model of hypothyroidism, the number of fecal pellet output was reduced, reflecting a slow colonic transit, while the daily fecal output and stool volume were increased in hyperthyroid animals. Thyroid hormones, which are transported across the blood-brain barrier (11), have widespread influence on the central nervous system, including central modulation of

sympathetic neuronal activity. Thyroid

hormones have been reported to be localized within several nuclei of the adult rat brain (12) and changes in adrenergic receptor populations occur in association with changes in thyroid status (13-16). The predominant effect of the noradrenergic input on nonsphincteric gut

motility is inhibitory (17). Therefore, it can be speculated that reduced (3-adrenoreceptors in different regions of the gut leads to an increase in the rate of transit and diarrhea, a common complication in hyperthyroidism. On the other hand, enhanced sympathetic neuronal activity has been documented in hypothyroidism by

numerous procedures (18). Since (3-

adrenoreceptor activation is associated with a decrease in the rectosigmoid colonic pressure and colonic motility (19), the delay in colonic transit may be the cause of a constipated bowel

habit, which is a common feature of

hypothyroidism.

In the present study, the significantly decreased food intake in the hypothyroid rats may occur secondary to decreased colonic transit, via the reflex inhibition of gastric emptying (20-23). Consistent with this hypothesis, gastric emptying has been shown to be delayed in hypothyroid patients and the patients with eating disorders

(24). The delayed gastric emptying in

hypothyroidism may be associated with

increased activation of sympathetic inhibitory pathways, either via a cologastric reflex or a central mechanism. However, the gastric emptying rate was not changed in hyperthyroid rats. In contrast to our data, Holdsworth et al (25) observed a significant decrease in the gastric emptying rate of a liquid meal in patients with hypertyroidism at the point of achievement of euthyroidism. Nevertheless, the results of our study are in agreement with the observations of Jonderko et al (4), who have reported that gastric emptying of solids does not differ from that observed in age-matched healthy control subjects, suggesting that the abnormalities causing diarrhea in hyperthyroidism are primarily localized distally to the stomach. Moreover, it was shown in thyrotoxicosis that small and large intestinal transit is accelerated, while gastric emptying remains unchanged (26).

The results of the present study demonstrate that hypothyroidism alters the motility of both colon and stomach, while the motility change in hyperthyroidism is confined to the colon. Several mechanisms may be involved in alterations of gut motor activity induced by dysfunction of the thyroid gland, including a possible change in the population and distribution of (3-adrenoreceptors in various segments of the gut. Further

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