The Effect of Thyroxine on Biliary Motility

Abstract

Väitöskirjatyössä tutkittiin kilpirauhasen vajaatoiminnan yhteyttä sappitiekivien syntyyn.

Retrospektiivisessä potilastutkimuksessa todettiin sappitiekivipotilailla esiintyvän merkittävästi enemmän kilpirauhasen vajaatoimintaa kuin terveillä kontrollipotilailla tai sappirakkokivipotilailla. Eräs mahdollinen sappitiekivien synnylle altistava tekijä on sappitien sulkijalihaksen, Oddin sfinkterin, huonontunut toiminta. Vesihaudekokeissa osoitettiinkin kilpirauhashormonien vähentävän sappitien sulkijalihaksen supistumista, ja siten kilpirauhasen vajaatoiminnassa sappitien sulkijalihaksen toiminta voi olla puutteellista. Lisäksi eriasteisen kilpirauhasen toiminnan vaikutusta yleisesti sapen virtaukseen selvitettäessä todettiin, että kilpirauhasen vajaatoiminnan aikana sapen virtaus hidastui, ja se parani, kun kilpirauhashormonilääkityksen myötä kilpirauhasarvot normaalistuivat. Edelleen kilpirauhasen liikatoiminnassa sapen virtauksen todettiin nopeutuvan.

Johtopäätöksenä väitöskirjatyössä todettiin, että kilpirauhasen vajaatoiminnassa sappitien sulkijalihaksen toiminta saattaa olla puutteellista, mikä voi johtaa sappiteiden hidastuneeseen tyhjenemiseen ja siten edesauttaa sappitiekivien syntyä. Tuloksilla on tärkeä kliininen merkitys, sillä diagnosoimaton kilpirauhasen vajaatoiminta on erityisesti vanhemmilla naisilla varsin yleistä, ja siten sappitiekivipotilailta tulisikin tutkia myös seerumin kilpirauhasarvot, jotta myös mahdollinen sappitiekivien synnylle altistava tekijä tulisi hoidettua.

In the present study the association between common bile duct (CBD) stones and hypothyroidism was investigated, the finding leading to further studies regarding the effect of thyroxine (T4) on the human and pig sphincter of Oddi (SO) and the specificity and the mechanisms of this effect. The net impact of altered thyroid function on bile flow was studied both in the rat and in human subjects. The study consisted of two clinical and three experimental investigations.

In the retrospective study the CBD patients had significantly more diagnosed hypothyroidism compared to the gallbladder stone patients or to the age-, sex- and hospital admission-adjusted controls. The higher prevalence of hypothyroidism in the CBD stone patients compared to the gallbladder stone patients suggested that also factors other than merely changes in the cholesterol metabolism, or bile excretion rate, e.g. changes in the function of the SO, may be behind the association between CBD stones and hypothyroidism.

Ex vivo experiments with SO-rings were carried out in organ bath chambers. In the pig T4 did not affect on unspecific, high concentration KCl-induced SO contraction but did reduce the receptor-mediated ACh- and Hist-induced SO contraction, which suggested a direct effect of T4 on the control mechanisms of SO motility. Because the effect of T4 on the SO appeared to be prorelaxing, the absence of T4 might result in an increased tension in the SO. A similar prorelaxing effect of T4 on the SO contractility observed in the pig was found also in human SO specimens. This observation is thus not pig-specific , but may also be of clinical significance, as suggested by the association between diagnosed hypothyroidism and CBD stones. T4 had a direct prorelaxing effect on pig SO contractility also in physiological concentrations, and might thus influence SO tone also in vivo. In Western Blotting, the human SO expressed TR beta1 and beta2. The prorelaxing effect of T4 was mediated via a mechanism, which requires new mRNA and protein synthesis and subsequently leads to the activation of K+ channels.

The net impact of altered thyroid function on bile flow was studied both in the rat and in human. In rats net bile flow was studied by counting the relative intestine v. liver 99mTecnetium (Tc) HIDA activity of organs removed at various time points after 99mTc HIDA i.v. injection. The net bile flow to the duodenum was reduced in hypothyroidism and enhanced in hyperthyroidism. In patients 99mTc HIDA cholescintigraphy was performed in hypothyroid and euthyroid stage. The hepatic clearance was decreased and the hilum-duodenal transit time tended to be increased in the hypothyroid stage in the study patients, the appearance of radioactivity in the large bile ducts at the hilum, and hepatic maximal uptake being the same in the hypothyroid and the euthyroid stage. These findings further support the other findings that hypothyroidism might decrease bile flow into the duodenum.

In conclusion, the reduced prorelaxing effect of T4 on the SO in hypothyroidism may result in delayed emptying of the biliary tract, and, together with the possible cholesterol load in the bile and decreased hepatocytic excretion rate composes an important explanation for the increased association of CBD stones and hypothyroidism.