쿠싱증후군 환자에서 당 대사 이상 정도에 따른 인슐린 감수성과 인슐린 저항성의 변화

정인경,김성훈,정재훈,민용기,이명식,이문규,유형준,안규정,노정현,김동준,김광원 대한내분비학회 2003 Endocrinology and metabolism Vol.18 No.4

연구배경 당질 코르티코이드는 당 대사에 매우 중요한 호르몬으로 내인성 당질 코르티코이드 과다상태인 쿠싱증후군에서는 말초조직에서 인슐린 저항이 증가하고 이를 보상하고자 인슐린 분비의 증가로 고인슐린혈증이 동반된다고 보고되고 있다. 하지만 생체 내에서와 달리 시험관내에서는 췌도세포에 당질 코르티코이드를 장시간 처리하면, 인슐린 분비 및 생합성이직접적으로 억제됨이 확인된 바 있어 쿠싱증후군 환자에서 당뇨병의 원인으로는 아마도 말초조직에서 증가된 인슐린 저항성 뿐 아니라 이를 충분히 보상하지 못하는 췌장에서의 인슐린 분비 저하가 같이 동반되어있지 않을까 하는 가설을 세우게 되었고, 아직까지 당질코르티코이드가 당대사 이상을 일으키는 기전에 대해 쿠싱증후군을 당대사 정도에 따라 인슐린 감수성과 분비능을 분석한 연구는 없었기에 이를 알아보고자 하였다. 방법: 삼성서울병원에서 쿠싱증후군으로 진단 받은 환자 15명을 대상으로 하였다. 이에 대한 대조군으로는 쿠싱증후군 환자와 같은 성별 그리고 체질량지수를 갖은 15명의 건강한 성인을 대상으로 비교 하였다 쿠싱증후군 환자를 대상으로 경구당부하 검사를 통해 당대사 정도를 정상군, 내당능장애군, 그리고 당뇨병군으로 나눈 후 정맥 당부하 검사를 시행하여 각군의 인슐린 저항성과 인슐린 분비능의 지표를 비교하고, 수술 후 쿠싱증후군이 완치된 상태에서 수술 전후의 당대사 지표의 변화를 조사하였다. 결과: 1) 쿠싱증후군 환자 중 정상인은 20%, 내당능 장애는 27%, 그리고 당뇨병은 53%였다. 체질량지수, 나이, 그리고 발병 기간은 세 군간에 의미 있는 차이가 없었으나, 24시간 소변검사의 코르티솔 농도는 당뇨병군에서 의미있게 높았다. 2) 정맥당부하 검사 결과, 인슐린 감수성 지표인 Sl는쿠싱증추린」서 1.58±0.10[×10^(-4)(min^(-1)(μU/mL)^(-1)]로 정상 대조군의 3.37±0.49[×10^(-4)(min^(-1)(μU/mL)^(-1)]에 비해 의미있게 낮았으나(P=0.024), 쿠싱증후군 환자 중 NGT, IGT, DM 군간에 서로 통계적인 차이는 없었다. 3) SG는 정상 대조군과 쿠싱증후군 환자간에는 의미있는 차이가 없었고, 쿠싱 증후군에 있어서 당대사가 악화될수록 감소하는 경향을 보였으나 의미있는 차이는 없었다. 4) 인슐린 분비능의 지표인 AIRg는 정상인에 비해 전체 쿠싱증후군 환자의 경우 증가하는 경향을 보였으나 의미있는 차이는 없었다. 하지만 쿠싱증후군 환자중에서 당대사 상태에 따라 NGT군은 1299 (1297∼1310)(mu/g/min ×10^(-2))로 정상 대조군(368.9±98.6[mu/g/min ×10^(-2)]) 보다도 의미있게 높았고, DM군{202.2 (91.1~371.4) [mu/g/min ×10^(-2)}은 NGT군에 비해 의미있게 낮았다(P=0.0031). 5) 15명중 현재 완치 상태에 있는 6명에 대해 수술전과 후로 비교하였다. 수술 전 당대사 상태가 1명은정상, 1명은 내당능 장애, 그리고 4명은 당뇨병이었으나 수술 후 시행한 경구 당부하 검사상 모두 정상 당대사 상태를 보였다. 6) 수술 후 완치된 환자 6명에 있어 인슐린 감수성지표인 Sl는 수술전에 중앙값이 1.22[×10^(-4)(min^(-1)(μU/mL)^(-1)]로 대조군에 비해 의미있게 감고』어 있었으나(p.0.05), 수술후 10.95 [×10^(-4)(min^(-1)(μU/mL)^(-1)]로 정상 수준으로 회복되었고(P=0.0022), 인슐린 분비능을 나타내는 AIRg [mu/g/min ×10^(-2)] 값도 정상수준으로 회복되었다. 특히 인슐린 분비능의 회복양상은 혈당농도에 따라 판이하게 나타나서, 정상과 내당능장애 상태에 있던 2명은 수술전에 1201 [mu/g/min ×10^(-2)]로 증가되어 있던 AIRg 값이 수술 후 정상 수준으로 감소하였고, 수술 전에 당뇨병 상태에 있던 4명의 경우 245.9 [mu/g/min ×10^(-2)]로 인슐린 분비능이 감고il어 있었는데 이들은 수술 후 모두 정상 수준으로 증가되었다 (P=0.0286). 결론: 쿠싱증후군 환자에서 당대사 이상은 80%로 높은 유병률을 보였다. 모든 쿠싱증후군환자에서 인슐린 감수성은 정상인에 비해 저하되어 있어 말초조직의 인슐린 저항이 선행됨을 시사하며, 인슐린 분비능은 당대사의 정도에 따라 다르게 나타났는데, 정상 당대사군에서는 인슐린의 저항성을 극복할 만큼 정상 대조군보다 더 많은 양의 인슐린 분비를 하다가 고코르티솔혈증이 심할수록 인슐린 분비능의 감소로 당뇨병으로 진행됨을 확인할 수 있었고, 이런 인슐린 저항성과 인슐린 분비장애는 수술 후 다시 회복되는 가역적인변화를 보였다. Background: Glucocorticoid plays an important role in the control of carbohydrate metabolism. Patients with Cushing's syndrome have been reported to have an increased incidence of carbohydrate intolerance due to peripheral insulin resistance and hyperinsulinemia, although the exact incidence and nature of this disorder have remained unclear. Few results have been published about insulin resistance and insulin secretion according to the level of glucose concentration, or about the reversibility of such defects in patients with Cushing's syndrome. Methods: To assess the effect of glucocorticoid on the insulin sensitivity and insulin secretion in Cushing's syndrome, 15 patients with Cushing's syndrome were classified into 3 groups (normal glucose tolerance: NGT, impaired glucose tolerance: IGT, diabetes: DM) according to the degree of glucose tolerance based on the oral glucose tolerance test (OGTT). Insulin modified, frequently sampled, intravenous glucose tolerance test (FSIGT) was performed before and after curative surgery on these patients and on 15 healthy control subjects. Data were evaluated by non-parametric statistical analysis. Results: 1) Among the 15 patients with Cushing's syndrome, 3 (20%) were NGT, 4 (27%) IGT, and 8 (53%) DM, based on OGTT. Twenty-four hour urinary free cortisol (UFC) was significantly higher in the DM group. 2) Insulin sensitivity index (SI) of Cushing's syndrome was significantly lower than that of the control group p=0.0024), but was not significantly different among the three Cushing's syndrome groups of NGT, IGT and DM. 3) Glucose mediated glucose disposal (SG) (Ed- confirm this abbreviation; it does not seem to match the definition) of Cushing's syndrome was not significantly different from that of the control group. 4) Insulin secretion (AIRg) of Cushing's syndrome tended to be high, but it was not significantly different from that of control. However, according to the level of glucose concentration there was significant difference in AlRg among the three Cushing's syndrome groups p=0.0031); AIRg of DM was significantly lower than that of NGT. 5) After surgical treatment, parameters of insulin sensitivity and insulin secretion were normalized in 6 cured patients; 1 with NGT, 1 with IGT, and 4 with DM, preoperatively. Median SI of all 6 patients was significantly improved up to the normal range postoperatively p=0.0022). Median AIRg of these 6 patients was balanced around that of normal control postoperatively p=0.0286). Conclusion: Eighty percent of patients with Cushing's syndrome had abnormality of carbohydrate metabolism. Insulin sensitivity was significantly decreased in Cushing's syndrome. Insulin secretion was significantly higher only in the NGT and IGT groups of Cushing's syndrome. As the hypercortisolemia is exacerbated, insulin secretion is significantly decreased and causes DM, suggesting that glucocorticoid has a direct or indirect toxic effect on the pancreatic beta cell (J Kor SOC Endocrinol 18:392-403, 2003).

부신성 쿠싱씨 증후군의 부신절제술후 합병증

이재복 고려대학교 의과대학 1998 고려대 의대 잡지 Vol.35 No.2

Background : Adrenalectomy is needed in about 10 to 25% of Cushing's syndrome due to adrenal adenoma, hyperplasia or carcinoma. The purpose of this study is to compare the postoperative complications of adrenalectomy between the Cushing's and non-Cushing's patients. Method and Material : I collected the data of patients from July, 1987 to Jan, 1998 by the review of Korea University hospital chart. Comparison of the clinical data was made by statistical method. Results : Adrenalectomy was performed in 77 patients and the causes of adrenalectomy were primary aldosteronism(25 cases), pheochrmocytoma(23 cases). Cushing's syndrome(20 cases), adrenal carcinoma (5 cases), non-functioning adrenal adenoma(2 cases), ganglioneuroma(1 case) and neuroblastoma(1 case). The causes of Cushing's syndromes were adenoma(16 cases), nodular hyperplasia(3cases) and carcinoma(1 case) Approaches of adrenalectomy were anterior(60 cases), posterior(14 cases) and lateral(3 cases). Postoperative complications were atelectasis, pneumonia, wound infection, paralytic ileus. intra-abdominal abscess, intra-abdominal bleeding, acute renal failure and psychosis in order of frequency. The rate of postoperative complication in Cushing's syndrome was 85%, which was higher than the non-Cushing's rate, 31.6%(p=0.02). Respiratory complications, such as atelectasis and pneumonias were more common in postoperative complications of Cushing's syndrome (p=0.02). In patients of Cushing's syndrome, the development of postoperative complication was related with time of operation, size of tumor, weight of tumor, site of tumor, pathology and method of approach(p>0.05). Conclusion : The patients of Cushing's syndrome was prone to postoperative complications and the respiratory complications were the most common postoperative complications. Preoperative and postoperative careful respiratory management will reduce the complication of adrenalectomy in patients of Cushing's syndrome.

쿠싱 증후군에서 골밀도와 골교체율의 변화

박순희(Sun Hee Park),김선욱(Sun Wook Kim),이선화(Seon Hwa Lee),박도준(Do Joon Park),박경수(Kyong Soo Park),김성연(Seong Yeon Kim),조보연(Bo Youn Cho),이홍규(Hong Kyu Lee) 대한내과학회 2000 대한내과학회지 Vol.58 No.5

N/A Background : Although it is generally accepted that high serum glucocorticoid levels causes osteoporosis by suppressing the bone formation, conflicting results have reported on bone resorption. But, previous studies have been carried out in patients with glucocorticoid excess secondary to exogenous glucocorticoid treatment of disorders, which also affect bone turnover and mass by themselves. The purpose of this study were to assess the effect of glucocorticoid excess on bone mass and turnover not influenced by other diseases known to affect skeleton and by different gonadal status and sex and to study the reversibility of osteopenia after cure of Cushing's syndrome. Methods : We measured bone mineral density using dual energy X-ray absorptiometry(DEXA) in 28 patients with Cushing's syndrome before and after surgical cure. In addition, in the patients with Cushing's syndrome and 21 healthy premenopausal women matched for age, we measured biochemical bone markers. Results : 1) Marked osteopenia was present in most patients with active Cushing's syndrome. Lumbar spine BMD and Ward's triangle BMD were significantly lower than femoral neck BMD and femoral great trochanter BMD.(Z-score: lumbar spine -2.22±1.17, femoral neck -0.71±1.08, Ward's triangle -1.77±0.97, femoral great trochanter -0.64±0.71; mean±SD, p<0.05). In patients with active Cushing's syndrome, serum osteocalcin, a marker of osteoblastic function, was reduced(p<0.05), and bone resorption was increased, as indicated by increased urinary N-telopeptide(p<0.05). 2) Osteopenia was still in patients after surgical cure.(Z-score: lumbar spine -1.59±1.01, femoral neck -0.47±0.58, Ward's triangle -1.44±0.77, femoral great trochanter -0.42±0.61). In Cushing's syndrome patients after surgical cure, serum osteocalcin and urinary N-telopeptide were higher compared to controls but not stastistically significant(p>0.05). 3) When compared with pretreatment values, BMD after surgical cure of Cushing's syndrome was increased significantly(p<0.05). Serum osteocalcin was increased and urinary N-telopeptide was decreased significantly(p<0.05). Conclusion : These results show that compared to age matched control, premenopausal Cushing's syndrome patients have reduced bone formation, increased bone resorption, and reduced BMD, especially trabecular bone and that these abnormalities are improved after surgical cure.(Korean J Med 58:560-567, 2000)

Endogenous Cushing’s Syndrome in a Patient with Systemic Lupus Erythematosus

강은진,문수진,Kyung ho Moon,Deok-jae Han,Jain Lee,Sang Mi Ro,손장원,김성래,민준기,유순집 대한비만학회 2016 The Korean journal of obesity Vol.25 No.3

Systemic lupus erythematosus is an autoimmune disease for which glucocorticoids are the mainstay of treatment. Cushing’s syndrome is caused by glucocorticoid excess, which can be either exogenous or endogenous. Although iatrogenic Cushing’s syndrome is the most common form, especially in patients undergoing glucocorticoid treatment, endogenous glucocorticoid excess should be considered because it has a different treatment strategy. We describe a 51-year old woman with a longstanding history of SLE. She was treated with steroid and cytoxan pulse therapy and plasmapheresis. Her lupus activity had been stable for 7 years with low-dose glucocorticoid treatment. She showed excessive weight gain, easy bruising, moon facies, truncal obesity, acne, and menstrual disorder. Given her history of long-term steroid therapy, iatrogenic Cushing’s syndrome was considered the most likely diagnosis; however, worsening features of Cushing’s syndrome with a minimal dose of glucocorticoid led us to diagnose endogenous Cushing’s syndrome due to a left adrenal adenoma. The patient underwent laparoscopic left adrenalectomy. Her SLE was controlled with transient low-dose glucocorticoid treatment, and her lupus activity remained stable without glucocorticoid treatment. This is the first reported case of concomitant endogenous Cushing’s syndrome in a patient with preexisting SLE in Korea. This case shows the importance of differential diagnosis including exogenous Cushing’s syndrome and endogenous Cushing’s syndrome in autoimmune disease patients with glucocorticoid therapy.

의인성 쿠싱 증후군 환자에서 발생한 Kaposi 육종

백유상 ( Yoo Sang Baek ),신원웅 ( Won Ung Shin ),오태석 ( Tae Seok Oh ),손수빈 ( Soo Bin Son ),송해준 ( Hae Jun Song ),오칠환 ( Chil Hwan Oh ) 대한피부과학회 2011 대한피부과학회지 Vol.49 No.7

Kaposi`s sarcoma (KS) is a multifocal proliferative vascular tumor involving cutaneous and extra-cutaneous tissues. KS has been reported in patients treated with immunosuppressive agents for autoimmune diseases. However, KS has rarely been reported in patients with iatrogenic Cushing`s syndrome. A 77-year-old woman was evaluated with multiple asymptomatic violaceous nodules and plaques on both lower legs. She had been diagnosed with iatrogenic Cushing`s syndrome and had been treated with low-dose corticosteroid replacement therapy for >10 years. A histopathologic study showed extensive vascular proliferation in the dermis with spindle-shaped cells. Immunohistochemical staining for CD31, CD34, human herpesvirus (HHV)-8, and D2-40 was positive. We hereby report a case of KS in a patient with iatrogenic Cushing`s syndrome.

임산부에서 발생한 쿠싱병 1예

김정태,성문혁,박우리,한정호,한혜숙,심영광,오태근,전현정 대한내분비학회 2011 Endocrinology and metabolism Vol.26 No.4

Developing Cushing’s syndrome during pregnancy is rare because menstruation is irregular and hypercortisolism causes infertility. Developing Cushing’s disease during pregnancy is very rare because there is even less ovulation than those with the adrenal adenoma. The clinical manifestations of Cushing’s syndrome may easily be missed during pregnancy as the features of weight gain, hypertension,and hyperglycemia overlap with those that occur during a pregnancy. Diagnosing Cushing’s syndrome during a pregnancy is complex because the biochemical features are obscured by the natural changes in the hypothalamic-pituitary-adrenal axis that occur during pregnancy. Having Cushing’s syndrome during a pregnancy results in increased fetal and maternal complications,so early diagnosis and treatment are critical. We report the clinical and endocrine findings of a pregnant women with Cushing’s disease who underwent transsphenoidal surgery after delivery.

Cushing s syndrome을 동반한 Ludwig s angina 환자에 대한 치험례 : 증례보고

이동근(Dong Keun Lee),김용완(Yong Woan Kim),이은영(Eun Young Lee),박화규(Hwa Kyu Park) 대한구강악안면외과학회 1998 대한구강악안면외과학회지 Vol.24 No.4

Ludwig s angina is a serious and potentially life threatening infectious disease involving all of the submental, submandibular, and sublingual space bilaterally. It is characterized by severe swelling and broad-like induration of the tissues in the submandibular region and elevation of the tongue and floor of mouth with partial immobilization of these structures. A common cause of Cushing s disease is an iatrogenic problem related to chronic administration of either ACTH or glucocorticoids. Patients who administrated glucocorticoids altered response infection and wound healing. More important, many patients who are taking or have been taken glucocorticoids have risk of developing acute adrenal insufficiency (adrenal crisis) when place in stressful situation. The treatment of infections in Cushing s syndrome are reduction of number of microbes through the use of appropriated antimicrobial agents and proper surgical drainage and appropriated airway management and proper steroids therapy that increased administration of glucocorticoids. In this paper, we report a rare case of Ludwig s angina with Cushing s syndrome. A 45-years old women was referred to our clinic in November 1996 for treatment of infetious disease. Clinical examination of this patient showed a painful swelling of submental space, elevation of tongue and difficulty of respiration or Moon Face , Bufallo hump , striae of abdomen and ecchymosis of extremities. We treated through the quickly airway management using blind oroendotracheal intubation, antimicrobial injection of large quantity, increased administration of glucocorticoids and proper surgical drainage. And We aquired satisfactory result.

Forkhead box O3 plays a role in skeletal muscle atrophy through expression of E3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing’s syndrome

Kang, Seol-Hee,Lee, Hae-Ahm,Kim, Mina,Lee, Eunjo,Sohn, Uy Dong,Kim, Inkyeom American Physiological Society 2017 AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND M Vol.312 No.6

<P>Cushing's syndrome is caused by overproduction of the adrenocorticotropic hormone (ACTH), which stimulates the adrenal grand to make cortisol. Skeletal muscle wasting occurs in pathophysiological response to Cushing's syndrome. The forkhead box (FOX) protein family has been implicated as a key regulator of muscle loss under conditions such as diabetes and sepsis. However, the mechanistic role of the FOXO family in ACTH-induced muscle atrophy is not understood. We hypothesized that FOXO3a plays a role in muscle atrophy through expression of the E3 ubiquitin ligases, muscle RING finger protein-1 (MuRF-1), and atrogin-1 in Cushing's syndrome. For establishment of a Cushing's syndrome animal model, Sprague-Dawley rats were implanted with osmotic minipumps containing ACTH (40 ng.kg(-1).day(-1)). ACTH infusion significantly reduced muscle weight. In ACTH-infused rats, MuRF-1, atrogin-1, and FOXO3a were up-regulated and the FOXO3a promoter was targeted by the glucocorticoid receptor (GR). Transcriptional activity and expression of FOXO3a were significantly decreased by the GR antagonist RU486. Treatment with RU486 reduced MuRF-1 and atrogin-1 expression in accordance with reduced enrichment of FOXO3a and Pol II on the promoters. Knockdown of FOXO3a prevented dexamethasone-induced MuRF-1 and atrogin-1 expression. These results indicate that FOXO3a plays a role in muscle atrophy through expression of MuRF-1 and atrogin-1 in Cushing's syndrome.</P>

Cushing 증후군 2예 : 부신피질 선종으로 인한 due to Adrenocortical Adenoma

전영빈,이의용,김면호,박호진,유건,왕희정,이혁상,고일향 인제대학교 1984 仁濟醫學 Vol.5 No.3

Cushing's syndrome is the clinical and metabolic disorder resulting from a chronic excess of glucocorticoids. Approximately 20-25% of patients with Cushing's syndrome have primary overproduction of cortisol and other adrenal steroids due to an adrenal neoplasm. We recently experienced two cases of Cushing's syndrome due to adrenocortical adenoma. The diagnosis was confirmed by clinical features, biochemical, hormonal and radiological studies and finally pathologic examination. A brief review of literature was presented and our cases were reported.

Multiple Opportunistic Infections Related to Hypercortisolemia due to Adrenocortical Carcinoma: A Case Report

Song Byeong Geun,Lim Min Gi,Bae Joo Hwan,Hong Joo Hyun,Lee Sang-Geul,Park Se Hoon,강철인 대한감염학회 2021 Infection and Chemotherapy Vol.53 No.4

Cushing's syndrome is characterized by excessive cortisol and immuno-suppression. We experienced a case of Cushing's syndrome caused by adrenocortical carcinoma that was complicated by multiple opportunistic infections. A 37-year-old woman with adrenocortical carcinoma (ACC) presented with decreased mental ability and high fever one week after undergoing chemotherapy. Her initial blood culture revealed methicillin-resistant Staphylococcus aureus (MRSA) bacteremia accompanied by septic pneumonia. We admitted her to the intensive care unit and treated her for invasive pulmonary aspergillosis (IPA), Pneumocystis jirovecii pneumonia (PJP), candidemia, and Stenotrophomonas maltophilia pneumonia with broad-spectrum antibiotics and antifungal agents. Nevertheless, her clinical course worsened and she died. Herein, we report a case of Cushing's syndrome associated with cortisol-secreting ACC that presented with multiple opportunistic infections, including MRSA bacteremia, septic pneumonia, candidemia, PJP, and IPA, illuminating a relationship between hypercortisolemia and opportunistic infections.