Corticosteroids가 간세포 및 담즙분비에 미치는 영향

Abstract

[한글]

[영문]

It is evident by clinical observation that the jaundice of hepatitis often

decreases rapidly following the administration of adrenocorticosteroids. Patterson,

et al. studied this problem directly and concluded that cortisone possesses

choleretic and hydrocholeretic capacities. Against this interpretation are several

studies which have not confirmed a choleretic effect. However, the observation of

Gans and McEntee that repeated administration of large doses of prednisolone

resulted in an increase in hepatic bile flow is of interest. They also observed a

peculiar hepatic lesion characterized by the presence of large areas of vacuolar

degeneration in liver sections from the prednisolone treated animals. the present

study was performed to explore the status of hepatic bile secretion as well as

liver cell during the chronic administration of glucocorticoids or other steroids,

using secretory stimulants or histologic technique.

Mongrel dogs of both sexes, weighing 8 to 14 kg were employed in this experiment

and divided into following groups:

Group 1. Control: 10 dogs served as nontreated controls.

Group 2. Glucocorticoid treated: 17 dogs were used. Cortisone acetate,

prednisolone, or dexamethasone was administered intramuscularly to each subgroup of

three dogs for 10days, at a daily dose of 8.0mg/kg, 2.0mg/kg and 0.4mg/kg,

respectively. In addition three adrenalectomized dogs and five prednisolone treated

animals for successive liver biopsies were used.

Group 3. Desoxycorticosterone treated: Desoxycorticosterone acetate(DOCA) was

administered intramuscularly to a group of three dogs for 10days, at a dose of

4.0mg/kg daily.

Group 4. Testosterone treated: Testosterone propionate was administered at a dose

of 8.0mg/kg daily as Group 3.

At the end of the experimental period, food was withheld from each dog for 15

hours. Each dog was then anesthetized with sodium pentobarbital and the trachea was

cannulated. A laparotomy was performed. The cystic duct was ligated and a

polyethylene tube of an appropriate size(PE 190, Glay-Adams Co.) was passed into

the common duct and ligated securely in place. Physiological saline solution, pH

8.0, was infused throughout the experiment. Hepatic bile collected for one hour and

then bile samples were obtained following secretory stimulants such as secretin, 10

u. pancreozymin 10 u, and 100mg of cholates, e.g., sodium taurocholate, sodium

cholate or sodium desoxycholate.

Samples of bile were taken during 2 consecutive 10 minute periods following the

administration of the secretory stimulants.

Bile acid and bilirubin content were determined according to the methods of Irvin

et al. and Magee et al., respectively. Total bile acid and bilirubin outputs in

bile have been expressed in terms of mg per 10 kg of body weight per 10 minutes.

Serum amylase and lipase were determined by the methods as those described

previously(Hon et al). The methods for serum GOT, GPT, or Alkaline Phosphatase were

followed by the technique described in Sigma Bulletin. Glycogen content were

determined by the Anthrone Adapted method. The liver strips were dried in the oven

at 80℃ to constant weight. Ash was obtained following 24 hrs incubation in furnace

at the temperature of 800°-1,000℃.

Results

Hepatic bile flow: Although the total bile acid and bilirubin in hepatic bile

following the installation of total biliary fistulas in dogs decreased with a time

course, the bile flow during early 2 to 3 hous after preparation was relatively

consistence.

The administration of corticosteroid to dogs did not accompany any observable

responses except an irrespectable minor changes of body weight. However, a

significant changes of hepatic file fow and bile acid content in response to

secretory stimulants were noticed in glucocorticoid-treated animals.

In control animal the bile flow was increased following secretin or pancreozymin

stimulation and both the bile flow and bile acid content were significantly

increased by the stimulation with the choleretics, taurocholate and cholate. After

treatment with DOCA the flow increase was marked but bile acid content was greatly

reduced.

Following administration of glucocofrticoid for 10 days the bile flow in response

to secretin or pancreozymin was increased more than double folds in comparison with

that of control values, but the bile acid content in bile were essentially

unchanged. The response of bile flow induced byu the choleretics, particularly by

sodium cholate was enhanced in glucocorticoid-treated animals. Unlike control in

these animals bile acid content in bile was not raised by the taurocholate

administration.

In DOCA treated group the bile secretion after various secretory stimulation was

approximately similar to that seen in cortisone-treated animal. The response of

bile secretion in testosterone-treated animals showed little difference from

control and the flow was rather erratic.

Hapatic weight: The weight of the liver as a fraction of body weight in the case

of animals receiving glucocorticoids daily for 10 days was significantly increased

to 46.4g/kg body weight from the control value of 37.8g/kg body weight. The hepatic

weight was also increased in the adrenalectomized animals receiving supplementary

cortisone for 2 weeks. The testosterone-treated animals or DOCA treated animals

showed reduction of liver weight.

The weight of pancreas was relatively constant in all animals and the weight of

the kidney was decreased slightly in case of prednisolone, dexamethasone, DOCA

treated animals and adrenalectomized animals with supplementary cortisone.

Histological findings: Histological examination revealed in case of animals

receiving glucocorticoids a peculiar changes characterized by the presence of large

areas of ballooning and vesicular changes in liver. Special stain demonstreated

that the material distending the hepatic cells are glycogen. When serial biopsies

were taken the appearance of vesicular changes in liver cell was increased during

prednisolone administration and it faded rapidly after stopping the treatment. The

glycogen content in liver was increased during prednisolone treatment and decreased

after cessation of treatment same as the changes in the hepatic cells. The

ballooning and vesicular cytoplasmic changes in liver were observed in cortisone,

prednisolone and dexamethasone-treated animals but not in the normal control,

testosterone-treated or DOCA injected animals. The degrees of the change were most

marked in dexamethasone-teated animals and followed by prednisolone and

cortisone-treated animals.

Summary

1. The administration of glucocorticoids to dogs resulted in a significant

increased in the hepatic bile secretion in response to secretory stimulants.

2. The secretory response of hepatic bile in testosterone-treated animals was not

changed and the response was increase in DOCA-treated animals.

3. A significant increase of liver weight was induced by the animals receiving

glucocorticoids for 10 days. Other organ weights were not changed by the steroid

treatment except slight reduction of kidney weights in prednisolone, dexamethasone,

DOCA treated animals as well as adrenalectomized animal supplemented with

cortisone.

4. The presence of large areas of ballooning and vesicular changes of liver cell

was seen in glucocorticoid-treated animals, particularly in cases of dexamethasone

and prednisolone adminstration. Both vesicular changes of liver cell and liver

glycogen content were increased by the repeated administration of prednisolone and

reduced by the cessation of treatment. Special stain and liver glycogen

determination demonstrated the material distending the liver cell was glycogen.

These findings indicate that chronic administration of glucocorticoid results in

choleretic and hydrocholeretic actions, and increases liver weight and hepatic

glycogen content.(Supported by grant No. 65-7847, China Med. Board of New York)