대퇴골두의 저혈성괴사에 관한 실험적 연구

Abstract

[한글]매년 대퇴골두의 저혈성( 血性) 괴사를 유발하는 더 많은 종류의 질병들이 보고되고 있다. corticosteroid로 인한 대퇴골두의 저혈성괴사는 최근 장기이식후 다량의 steroid를 장기간에 걸쳐 사용하게 됨으로서 그 발생 빈도가 더 높아졌고 1957년 이래 185증례

이상이 문헌상에 보고되었다.

대퇴골두의 저혈성괴사를 일으키는 병인론은 첫째, 연골하 골조송증 및 미세골절로 인하여 골의 함궤 및 국소적인 저혈성괴사가 초래된다는 설, 둘째, 지방전색물질이 연골하 혈관을 폐쇄하므로서 저혈성괴사가 초래된다는 설 등이 있다.

본 연구는 대퇴골두의 저혈성괴사의 병인론을 더 자세히 알고자 시행하였다.

실험동물로서는 체중이 2.0kg 내외의 한국산 웅성백색가토 108마리를 사용하였으며 다음과 같이 네군으로 나누어 실험하였다.

제Ⅰ군: cortisone acetate를 매일 체중 kg당 3mg씩 근육내주사

제Ⅱ군: cortisone acetate를 매일 체중 kg당 6mg씩 근육내주사

제Ⅲ군: cortisone acetate를 매주 체중 kg당 21mg씩 근육내주사

제Ⅳ군: 무처치 대조군

무처치 대조군 및 실험군 동물은 1, 3, 6, 9, 12, 16, 20주에 각각 3마리씩 도살하여 체중의 변화, 혈청내 지방량 측정, 골의 X-선 소견, 대퇴골두(H-E 및 oil red O염색), 간(H-E, PAS 및 oil red O염색)의 병리조직학적 변화를 관찰한 결과 다음과 같은 결론을 얻었다.

1. 가토에 cortisone actate를 투여하여 과지방혈증 및 지방간이 유발됨을 관찰하였다.

2. 폐포벽에 있는 모세혈관에 지방전색이 발생되었다.

3. 대퇴골두에서 연골하 모세혈관에 지방전색이 야기되고, 골조송증이 발생되며 골소강내 골세포의 소실이 유발되었다.

4. 위의 변화는 과량의 cortisone acetate를 투여할 때에 더욱 심하고 또한 조기에 발생되었다.

이상의 소견으로 미루어 보아 과지방혈증으로 인한 연골하 모세혈관의 지방전색은 cortisone 투여로 대퇴골두에 유발되는 저혈성괴사의 주요원인의 하나가 될 수 있다고 사료되었다.

[영문]Each year more and more cases of different diseases in which avascular necrosis is seen are being reported and circumstantial evidence accumulated since 1957 has implicated corticosteroids as an etiological factor in aseptic necrosis of bone. The increased use of long-term systemic steroid therapy in recent years, especially in the field of organ transplantation, has made this a well-known complication and over 185 cases have previously been reported in the world literature. Especially in Korean, there are many problems as a result of using corticosteroids in arthritic

patients.

The pathogenesis of corticosteroid induced avascular necrosis is still a matter of considerable controversy. Current thought seems to have crystallized around two totally unrelated theories; that of subchondral osteoporosis and micro-fracture leading to bone collapse with localized aseptic necrosis: and that of fat embolism which postulates subchondral vascular occlusion by peripheral fat emboli.

The present study attempts to define more precisely the pathogenesis of corticosteroid-induced avascular necrosis of the femoral head.

Materials and Methods

Korean albino rabbits, 108 healthy males averaging 2.0Kg. of body weight were used. They were maintained in the laboratory on the same diet, humidity and temperature for 2 weeks pre-experimentally. Base-line values were obtained for serum cholesterol, phospholipids, and triglycerides(Fasting animal; blood obtained by cardiac puncture).

Rabbits were divided into four groups and treated as follows:

Group 1: Cortisone acetate(3mg/kg/day, IM)……20 rabbits

Group 2: Cortitone acetate(6mg/Kg/day, IM)……29 rabbits

Group 3: Cortisone acetate(21mg/kg/week, IM)……20 rabbits

Group 4 Normal control……21 rabbits

Cortisone acetate was administered intramuscularly in a dose of 3 mg per Kg. of body weight daily in group 1, 6 mg per Kg. of body weight daily in Group 2, and 21 mg per Kg. of body weight weekly in Group3.

Because of the high infection rate in steroid-treated animals, all rabbits were give intramuscular injections of benzathine penicillin, 600,000 units, weekly in single doses. Three rabbits of each group were sacrificed in the following time sequence; first, third, sixth, ninth, twelfth, sixteenth, and twentieth weeks.

The animals were not fed for 18 hours before sacrifice and blood samples were taken for serum cholesterol, phospholipid, and triglyceride determinations.

At the time of sacrifice, each rabbit was weighed, roentgenograms were taken, and the liver, lung and femoral head were removed for histological examination.

Gross and histologic studies were performed on the liver using hematoxylin and eosin, PSC, and oil red O stains and on the lung using hematoxylin and eosin and oil red O stains. Femoral heads were bisected in the coronal plane. One-half was prepared for histological examination with hematoxylin and eosin. The other half was fixed in neutral formalin for at least 24 hours, embedded in gelatin, and hardened again in formalin. These blocks were then sectioned at 5 microns in a cyostat. Sections were stained for 15 minutes with oil re O and counterstained for 30 seconds with aqueous hematoxylin.

Results

1. A weight loss was observed in all corticosteroid-treated animals and its rate was increased with duration of corticosteroid treatment and greatest in Group. 2. All control animals gained weight.

2. Serum cholesterol, phospholipids, and triglycerides were increased in the steroid treated animals except for triglyceride in Group 1 and phospholipid in Group 3. In control animals, serum lipids did not vary significantly from pretreatment values.

3. There was roentgenographic evidence of osteoporosis and atrophy by the first week, peak in the sixth week, and femoral head was collapsed by the ninth week.(The degree of osteoporosis was checked by using a photodensitometer.) No such changes

were apparent in control animals.

4. Accumulations of fat appeared at periportal area in the first week, peaking in the sixth week, and then decreased gradually. Ballooning of th live cell associated with vacuoles was severe in Group 2. The control group showed no change.

5. Pulmonary fat emboli occurred by th third week in corticosteroid-treated animals. Emboli were found within the endothelial-lined capillaries. These changes became diffuse by the ninth week. No control animals had lipid materials in Jung

sections.

6. On hematoxylin and eosin stains, osteoporosis appeared by the third week and became more severe between the sixth and ninth week.

Focal osteocytic death was observed at the sixth week, and increased by the twelfth week. With oil red O stains fat emboli were found within subchondral capillaries at the third week, they were maximum by the ninth week, and had decreased by the sixteenth week.

Summary

As a result of increased in serum lipids and development of fatty liver, fat embolization to the lung and bone occurred. The significant increase in focal osteocytic death suggests that fat embolization to bone resulted in vascular obstruction, and the fat embolization to bone may be one of main factors of aseptic

nectosis of bone. These change wer prominent in the group with a high dose of corticosteroid in the early stage of the experiment.