Possible mechanism and treatment of o,p'DDD-induced hypercholesterolaemia.

Ortho,para,dichlorodiphenyl dichloroethane (o,p'DDD, Mitotane (Roussell)) is used as an adrenolytic drug to reduce adrenocortical mass and circulating cortisol levels in Cushing's syndrome but has the unwanted side-effect of inducing hypercholesterolaemia. This paper examined the mechanism of that effect in 30 patients with Cushing's syndrome treated with o,p'DDD during the past 10 years. o,p'DDD increased serum cholesterol by 68 per cent, mainly by increasing LDL-cholesterol. The latter effect was not due to impaired binding of LDL to its receptor, as shown in vitro using cultured fibroblasts. Increases in plasma mevalonic acid during o,p'DDD administration were suggestive of increased cholesterol synthesis, this effect being reversed by simvastatin. These findings suggest that o,p'DDD causes hypercholesterolaemia by increasing cholesterol synthesis. It is proposed that this effect is due to the drug's known ability to block cytochrome P450-mediated reactions, thus impairing the formation of oxysterols responsible for down-regulating hepatic cholesterol synthesis. Treatment with simvastatin, an inhibitor of cholesterol synthesis, reverses the hyperlipidaemia and enables o,p'DDD therapy to be maintained without increasing cardiovascular risk.     

Possible Mechanism and Treatment of o,p'DDD-induced Hypercholesterolaemia

Ortho, para, dichlorodiphenyl dichloroethane (o,p'DDD, Mitotane(Roussell)) is used as an adrenolytic drug to reduce adrenocorticalmass and circulating cortisol levels in Cushing's syndrome buthas the unwanted side-effect of inducing hypercholesterolaemia.This paper examined the mechanism of that effect in 30 patientswith Cushing's syndrome treated with o,p'DDD during the past10 years. o,p'DDD increased serum cholesterol by 68 per cent, mainly byincreasing LDL-cholesterol. The latter effect was not due toimpaired binding of LDL to its receptor, as shown in vitro usingcultured fibroblasts. Increases in plasma mevalonic acid duringo,p'DDD administration were suggestive of increased cholesterolsynthesis, this effect being reversed by simvastatin. These findings suggest that o,p'DDD causes hypercholesterolaemiaby increasing cholesterol synthesis. It is proposed that thiseffect is due to the drug's known ability to block cytochromeP450-mediated reactions, thus impairing the formation of oxysterolsresponsible for down-regulating hepatic cholesterol synthesis.Treatment with simvastatin, an inhibitor of cholesterol synthesis,reverses the hyperlipidaemia and enables o,p'DDD therapy tobe maintained without increasing cardiovascular risk.     

Psychiatric aspects of Cushing's syndrome

Patients with Cushing's syndrome were studied (n=209, 78% females). Control patients had pituitary adenomas secreting growth hormone or prolactin. Age at diagnosis of Cushing's syndrome was 8-74 (mean 39) years. Duration of symptoms was 0.2-9 (median 2.0) years. Adverse life events within the 2 years preceding the onset of Cushing's syndrome were not significantly commoner than in controls. Depressive illnesses were associated with the presence of adverse life events (p<0.001). Depressive illness was more common in females (p<0.01). There were no significant differences in the severity of depression in the different types of Cushing's syndrome. Pathological anxiety had been diagnosed in 26 patients (12%), mania or hypomania in six patients (3%) and confusion in three patients (1%). Psychotic illness had been diagnosed in 16 patients (8%) and was more common in adrenal carcinomas (p<0.01). Significant psychiatric illness, usually depressive preceded the onset of all symptoms and signs of Cushing's syndrome in 25 patients (12%); 23 of these developed pituitary Cushing's disease, and two adrenal adenomas. When Cushing's syndrome was diagnosed, significant psychiatric illness, usually depression, was present or had been a feature of Cushing's syndrome in 120 (57%) patients.      

The Treatment of Cushing's Disease by Trans-sphenoidal Hypophysectomy

Thirteen patients aged 24 to 65 with Cushing's disease havebeen treated by tranfssphenoidal hypophysectomy. There was oneincident of meningitis and one late death from myocarditis.No radiotherapy was given. In 12 patients pituitary histologyshowed Crooke's changes and an adenoma was present in seven.On review of the 12 survivors two to 11 years later, 11 arein complete remission. One patient still showed some clinicalfeatures of Cushing's syndrome but steroid levels were normal.In five of the seven premenopausal women normal menstruationhas returned and pregnancy has occurred in three. In four patientsreplacement hormone therapy is no longer required and a furtherfour take only partial treatment. We conclude that transsphenoidalhypophysectomy is an effective treatment for Cushing's disease.     

Insulin resistance in pituitary, thyroid, and adrenal diseases

Patients with acromegaly, Cushing's syndrome, and Graves' disease often have impaired glucose tolerance with high insulin secretion. Persistent elevation of serum GH levels has insulin-antagonistic effects on peripheral tissues. The number of insulin receptors on monocytes is decreased in patients with acromegaly. The expression of GLUT-1 glucose transporters is also decreased in GH-treated adipocytes in vitro. Insulin resistance in patients with Graves' disease may be due to antagonism between the effect of insulin and hyperthyroidism at the hepatic level. Glucocorticoids also have insulin-antagonistic effects on both hepatic and extrahepatic tissues, although the precise mechanism still remains to be elucidated. Insulin resistance in these patients can be improved after successful treatment of their endocrine diseases.     

Changes of platelets, serum lactic dehydrogenase, gamma-glutamyltranspeptidase, choline esterase and creatine phosphokinase levels in patients with Cushing's syndrome

In order to identify non-endocrine laboratory tests of diagnostic value in Cushing's syndrome, we measured platelet counts and serum myogenic and hepatic enzyme levels in 10 patients with Cushing's syndrome and compared the findings with those of 15 obese patients without Cushing's syndrome. Patients with Cushing's syndrome had increased numbers of platelets, moderately elevated serum lactic dehydrogenase and gamma-glutamyltranspeptidase levels, and significantly lower creatine phosphokinase and choline esterase activities compared with those of obese control patients. We concluded that when several of these abnormal values were seen in obese patients the levels of suspicion for Cushing's syndrome should be high.     

Cushing's disease treated by total adrenalectomy: long-term observations of 43 patients

Forty-three patients were treated by total adrenalectomy for pituitary-dependent Cushing's disease. The median period of observation was 10 years (range one to 20 years). Thirty-eight patients (88 per cent) had rapid and lasting remissions. Of the 38 in remission, 21 became pigmented but without pituitary enlargement, 11 became pigmented with evidence of further pituitary expansion (Nelson's syndrome) and six neither became pigmented nor showed pituitary expansion. Pituitary expansion was associated with high plasma ACTH values, and treatment of pituitary tumours by surgery or radiotherapy gave poor results. However, when compared with alternative methods of treatment, total adrenalectomy for Cushing's disease is still satisfactory for many patients, despite advances in pituitary surgery, and has advantages over 'medical adrenalectomy' with drugs.     

Medical treatment for Cushing's syndrome

Systemic cortisol plays an important role in the metabolism of glucose, lipids and proteins, as well as in the regulation of electrolyte balance. It is well known that the development of the microvascular disease of various organs such as the heart and kidney, in patients with diabetes mellitus, hyperlipidemia and hypertension of which disorders are frequently associated with Cushing's syndrome. Thus, we should treat Cushing's syndrome as soon as possible, since many complications, including cardiovascular diseases and infections, will soon occur when the definite diagnosis is delayed. Adrenalectomy is essential for treatment for Cushing's syndrome even in the patients with pituitary or ectopic ACTH-producing tumor. Some case can not be treated with surgical procedures because of worsened conditions with several complications of infection and diabetes. Then we choose medical treatment. Medical adrenalectomy is achieved by using with mitotane which is usually used for adrenocortical cancer. We commonly treat the patients with Cushing's syndrome due to adrenal tumor and pituitary or ectopic ACTH producing tumor by using metyrapone which mainly inhibits 11-hydroxylase. Metyrapone is also recommended to treat the patients who are not well differentiated Cushing's disease from ectopic ACTH syndrome. We rarely use trilostane which is an inhibitor against 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Replacement therapy with hydrocortisone should be considered if adrenal failure will occur during treatment with those drugs.     

An evaluation of the distinction of ectopic and pituitary ACTH dependent Cushing's syndrome by clinical features, biochemical tests and radiological findings

The efficiency of various laboratory and radiological investigations in the differentiation of ectopic from pituitary dependent Cushing's syndrome was studied, based on findings in 23 patients with verified Cushing's disease and seven patients with the ectopic ACTH syndrome. Clinical features strongly favouring the ectopic type were male sex and history for less than 18 months. Basal biochemical features strongly indicating the ectopic syndrome included plasma K+ less than 3.0 mmol/l and HCO3 greater than 30 mmol/l; serum cortisol at 9 a.m. or midnight of greater than 800 nmol/l; urine free cortisol greater than 1300 nmol/24 hours; plasma ACTH greater than 100 ng/l. In the high-dose dexamethasone suppression test, suppression by less than 50 per cent of 9 a.m. serum cortisol, urine free cortisol or 17-oxogenic steroids was usually indicative of an ectopic source of ACTH. A mean suppressed value of greater than 450 nmol/l for the 9 a.m. and midnight cortisol combined occurred in all of those with the ectopic syndrome, but in none of the 23 patients with Cushing's disease. For urine free cortisol, a mean suppressed value of less than 1000 nmol/24 hours was found in all patients with Cushing's disease, but in none of those in the ectopic group. In the metyrapone test, there was an increase of less than or equal to 3-fold in 11-deoxycortisol at 24 hours in patients with ectopic ACTH; the increase was greater than 3-fold in all but one of the patients with Cushing's disease. Failure to respond to either dexamethasone or metyrapone was found in only one of the patients with Cushing's disease (Patient 16); in the ectopic group, all patients except Patient D failed to respond to either test. It is concluded that patients presenting with clinically obvious Cushing's syndrome along with measurable plasma ACTH can be reliably divided by conventional tests into those that are driven from the pituitary and those driven by ectopic ACTH.     

甲状腺功能亢进症并肝损害的临床特征与治疗转归分析

目的总结甲状腺功能亢进症(甲亢)并肝损害的临床特征与治疗转归。方法回顾性分析2009年6月-2010年6月入院诊治的119例甲亢并肝损害患者(肝损害组)的临床特点与治疗转归资料,并与同期247例甲亢不伴有肝损害患者(无肝损害组)作比较。结果肝损害组占同期甲亢患者的30.4%,其中108例(90.8%)无明显肝损害的临床表现,以丙氨酸氨基转移酶和天门冬酸氨基转移酶升高为主,多为轻、中度升高;患者高代谢症候群、突眼、甲状腺肿大发生率及肿大程度明显高于无肝损害组,心率明显快于无肝损害组,血清游离三碘甲状腺原氨酸、游离甲状腺素及吸131I率明显高于无肝损害组,而体质量指数则明显低于无肝损害组(P<0.05)。两组性别、年龄、病程、甲亢类型、甲状腺球蛋白抗体及甲状腺微粒体抗体滴度差异无统计学意义(P>0.05)。肝损害组患者随访18个月以上,101例131I治疗患者随着甲亢控制,肝功能恢复正常,未见有再发肝损害;18例抗甲状腺药物治疗,其中10例随着甲亢控制,肝功能逐渐恢复正常;8例随着甲亢控制,肝功能逐渐恢复正常,但随着甲亢复发,再出现肝功能损害。结论肝损害是甲亢的常见并发症之一,其肝损害症状较轻,多数患者不典型,但并随甲亢病情较重。护肝治疗结合恰当的抗甲亢治疗预后良好。     

Normal and abnormal regulation of β-MSH in man

The regulation of plasma beta-melanocyte-stimulating hormone (beta-MSH) in man has been studied utilizing a radioimmunoassay previously described (1). In normal subjects plasma beta-MSH values ranged from 20 to 110 pg/ml. Metyrapone increased and dexamethasone decreased plasma beta-MSH levels. Surgical stress stimulated beta-MSH secretion. Plasma beta-MSH levels were elevated in patients with untreated Addison's disease and untreated congenital adrenal hyperplasia, and these levels fell to normal during glucocorticoid therapy. In patients with Cushing's syndrome due to pituitary adrenocorticotropic hormone (ACTH) excess, plasma beta-MSH was slightly elevated before treatment. In those patients who developed pituitary tumors and hyperpigmentation after bilateral adrenalectomy, plasma beta-MSH was greatly elevated. In patients with Cushing's syndrome due to adrenal tumor, plasma beta-MSH was subnormal. In patients with the ectopic ACTH syndrome, the levels of plasma beta-MSH were high. Plasma beta-MSH had a diurnal variation in normal subjects, patients with Addison's disease, and patients with congenital adrenal hyperplasia; but the normal diurnal variation was lost in patients with Cushing's disease. In patients with high plasma beta-MSH, simultaneous determinations of plasma ACTH showed close correlation between the degree of elevation of ACTH and that of beta-MSH. In extracts of tumors from patients with the ectopic ACTH-MSH syndrome the quantities of the two hormones were roughly equivalent. In patients with hyperpigmentation due to a variety of disorders other than pituitary-adrenal abnormalities, plasma beta-MSH was normal. It is concluded that the secretion of beta-MSH is regulated by the same factors that regulate ACTH.     

Rise in gamma-GT during anticonvulsive therapy

There have been several reports of the isolated occurrence of raised serum gamma GT levels in the course of long-term anticonvulsive treatment. The findings concerning the correlation between this elevation of gamma GT and various dimensions of epilepsy or treatment regimens are equivocal. In a retrospective study of 158 epileptics, the mean values of the serum gamma GT level have been grouped according to anticonvulsive regimen and compared with one another, as well as correlated to the serum concentration of the antiepileptic drug. An elevation of serum gamma GT was found in 103 patients. Among the different subgroups the mean value for serum gamma GT was raised in cases under treatment with PHT, PB or PRM. No such elevation was found in cases under monotherapy with CBZ or VPR. The elevation of serum gamma GT is considered to reflect hepatic enzyme induction rather than hepatic impairment.     

Sotalol for Atrial Tachycardias After Surgery for Congenital Heart Disease

Atrial tachycardias, in particular atrial flutter after surgery for congenital heart disease, is associated with a high mortality. Treatment with various antiarrhythmic drugs and/or antitachycardia pacemakers is not very successful. Sotalol, a Class III drug, has shown to be a promising drug in adults with atrial tachycardias. However, the experience with sotalol in children after surgery for congenital heart disease is limited. Therefore, we describe our results here. Between December 1990 and February 1997, 26 children with atrial tachycardias, most of them with atrial flutter or fibrillation (n = 20), after surgery for congenital heart disease were treated with sotalol orally. The age of the children at the start of treatment was 7.5 ± 5.8 years (mean ± SD). The time interval between surgery and the start of atrial tachycardia ranged from 1 day to 14.3 years (3.8 ± 3.8 years). Conversion to sinus rhythm was achieved in 16 out of 22 hemodynamically stable children with a dosage of 4.0 ±1.6 mg/kg per day. The six children without sinus rhythm on sotalol and four hemodynamically unstable patients were treated prophylactically with sotalol after DC cardioversion for their tachycardias. Two children complained of mild transient fatigue. Heart rate decreased during therapy (95 ± 33 vs 81 ± 21 beats/min; P = 0.01). QT_c-intervals did not change. Proarrhythmias such as torsades de pointes were not encountered. Two children with a preexis-tent sick sinus syndrome showed aggravation of bradycardia and needed pacemaker implantation. The percentage of children with a recurrence-free interval of 1 and 2 years was 96% and 81 %, respectively, for all atrial tachycardias, and 92% and 66% for atrial flutter. The recurrences of atrial tachycardias during the follow-up period, which ranged from 0.1-6.1 years (2.5 ± 1.8 years) could be treated with only an increase of the dosage of sotalol in all but one patient. We conclude that sotalol is an effective drug for the treatment and prevention of atrial tachycardia in children afler surgery for congenital heart disease.     

A phase I/II study of the safety and activity of a microsphere formulation of KNI-272 in patients with HIV-1 infection

Eighteen patients with symptomatic HIV disease were enrolled into a phase I/II study of a microsphere formulation of the HIV protease inhibitor KNI-272, with doses escalated up to a maximum dose of 60 mg/kg/day. One patient developed reversible elevation in hepatic transaminase. The plasma half-life of the drug was very short, varying between 0.25 and 1.1 h. No consistent effect on plasma HIV RNA levels or CD4(+) lymphocyte counts was seen.     

Fatal pulmonary thromboembolism after successful transsphenoidal hypophysectomy for Cushing's disease

We have reported the case of a 30-year-old woman with Cushing's disease who died of massive pulmonary thromboembolism 5 weeks after successful transsphenoidal hypophysectomy. Glucocorticoid excess appears to cause a hypercoagulable state, and consideration of this thromboembolic propensity and its potential duration after cure is indicated in all patients with Cushing's syndrome during the perioperative period. At the present time, we recommend the routine perioperative use of intermittent pneumatic compression in all patients with Cushing's disease or Cushing's syndrome.     

Cushing's Disease: TREATMENT BY PITUITARY IMPLANTATION OF RADIOACTIVE GOLD OR YTTRIUM SEEDS

Fifty-seven patients with Cushing's disease (pituitary-dependentCushing's syndrome), and four with Nelson's syndrome followingadrenalectomy, have been treated by implantation of ¹⁹⁸Au or⁹⁰Y seeds into the pituitary gland. Fifty-five of the Cushing'sdisease patients have been fully followed up with steroid testsfor 1 to 12 years after implant. They have been categorizedaccording to the X-ray appearance of the fossa before implant,which was the most important factor in predicting the outcome.The results were as follows: 1. Cushing's disease without evidence of pituitary tumour onX-ray (31 patients). One year after implant, 65 per cent ofthese patients were in complete remission and a further 16 percent in partial remission—a total of 81 per cent improved,without any other treatment. Only 34 per cent required replacementcorticosteroids, and 30 per cent replacement thyroxine. 52 percent needed no replacement hormone treatment. Only one patienthad relapsed more than 2 years after implant. 2. Cushing's disease with possible pituitary tumour on X-ray(10 patients). One year after implant, five of these were incomplete and one in partial remission. These remissions weremaintained. 60 per cent required replacement steroids or thyroxine. 3. Cushing's disease with definite X-ray evidence of pituitarytumour (14 cases). In only two of these was permanent remissionobtained by implant alone, despite the use of higher radiationdoses in most of them. In four the tumour showed X-ray or clinicalevidence of local invasion after implant, and three subsequentlyneeded surgical hypophysectomy. A combination of implant, adrenalectomy,hypophysectomy, or external irradiation was needed to controlthe disease in most of these patients; 10 required surgery ofpituitary or adrenals. Some degree of hypopituitarism occurredin them all and 64 per cent required replacement hormones asa result of pituitary or adrenal ablation. In the whole series of 61 patients implanted for either Cushing'sor Nelson's syndrome, there were six who developed serious problemsfrom local invasion by pituitary tumours despite various formsof treatment of the pituitary. This invasion contributed tothe deaths of four. 4. In all four cases of Nelson's syndrome, clinical remissionof pigmentation was evident within a year of implant. One patientlater required external pituitary irradiation and craniotomyto control his pituitary tumour, but survived 13 years. Theothers have been followed for three, four, and nine years withoutrecurrence. 5. Pituitary implant for Cushing's disease appears to be atleast as effective in producing remission as other treatmentsdirected at the pituitary, and is as effective in restraininggrowth of pituitary tumours. It is much more effective thanexternal irradiation. Though the cure of the Cushing's syndromeis not as certain as with adrenalectomy, the proportion of patientsrequiring replacement hormone therapy is approximately half,and the procedure of implant is a smaller surgical undertaking.The technical complications of implants, particularly cerebrospinalfluid rhinorrhoea, are minimal (5 per cent) and readily treatable.     

Parallel assays of beta-endorphin and ACTH in Cushing's patients undergoing petrosal sinus sampling

This study explores the possibility of improving endocrinologic testing during petrosal sinus catheterization by determining both beta-endorphin and corticotropin (ACTH). We studied 14 patients with Cushing's disease, two with adrenal tumor, and three with ectopic tumors secreting ACTH. In patients with Cushing's disease, beta-endorphin concentrations paralleled those of ACTH in all basal plasma samples collected either from petrosal sinuses or peripheral veins. Individual responses of beta-endorphin and ACTH to corticotropin releasing hormone (CRH) were closely related to the presence of a corticotroph adenoma. In such patients, a consistently higher concentration of beta-endorphin over ACTH was observed in all samples collected either from petrosal sinuses or peripheral veins; the ratios were unchanged after the administration of CRH. In patients with ectopic ACTH secretion, the mean ratio of beta-endorphin over ACTH (with both values expressed in pmol/L) was significantly higher (3.5) than that of patients with Cushing's disease (2.9) or Cushing's syndrome due to adrenal tumor (2.7).     

HCV in an HIV-infected man

A case is reported of a 31-year-old former IV drug user who had been using AZT for one year. Results of a routine blood test showed that the patient was positive for hepatitis C viral (HCV) antibodies. Over a 5-year period, he was treated with a variety of antiretroviral agents, some of which were stopped because of increased liver enzymes and high bilirubin levels. The patient died in the fifth year of treatment due to complications of advanced liver disease, including hemorrhage, hepatorenal syndrome, and hepatic encephalopathy. Since HCV is nearly universal in IV drug users, serology should be performed in all HIV-infected patients with any history of IV drug use or cocaine snorting, and on all patients with signs of liver disease. Physicians treating co-infected patients must also be aware of subtle signs of asymptomatic liver disease.     

Avascular necrosis of bone: a manifestation of Cushing's disease

Cushing's disease is endogenous hypercortisolism due to a pituitary adenoma. Although exogenous hypercortisolism is a well known cause of avascular necrosis and although there have been many reports of avascular necrosis associated with endogenous Cushing's syndrome, there has only been a single well documented case report associating avascular necrosis of bone with Cushing's disease. We report four new cases of avascular necrosis of bone in patients with well documented Cushing's disease.     

Long term use of piroxicam in the treatment of systemic lupus erythematosus.

Twelve patients suffering from systemic lupus erythematosus (SLE) were treated with piroxicam (Hotemin-EGIS) for 9-18 (mean: 13.7) months. At the beginning, the patients were in a moderately active stage of the disease, 10 patients also received low dose corticosteroid treatment. After the study was completed, clinical and immunological improvement was seen in 10 cases. The average daily dose of prednisolone could be reduced (from 10.5 mg to 5 mg). These patients tolerated the treatment well, no adverse effect was seen. No elevation of serum transaminase, creatinine or change in blood cell count and glomerular filtration rate were observed. Piroxicam, therefore, is recommended for the treatment of mildly active SLE.