Mortality in patients with Cushing's disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study.

BACKGROUND: No agreement has been reached on the long-term survival prospects for patients with Cushing's disease. We studied life expectancy in patients who had received curative treatment and whose hypercortisolism remained in remission for more than 10 years, and identified factors determining their survival. METHODS: We did a multicentre, multinational, retrospective cohort study using individual case records from specialist referral centres in the UK, Denmark, the Netherlands, and New Zealand. Inclusion criteria for participants, who had all been in studies reported previously in peer-reviewed publications, were diagnosis and treatment of Cushing's disease, being cured of hypercortisolism for a minimum of 10 years at study entry, and continuing to be cured with no relapses until the database was frozen or death. We identified the number and type of treatments used to achieve cure, and used mortality as our primary endpoint. We compared mortality rates between patients with Cushing's disease and the general population, and expressed them as standardised mortality ratios (SMRs). We analysed survival data with multivariate analysis (Cox regression) with no corrections for multiple testing. FINDINGS: The census dates on which the data were frozen ranged from Dec 31, 2009, to Dec 1, 2014. We obtained data for 320 patients with 3790 person-years of follow-up from 10 years after cure (female:male ratio of 3:1). The median patient follow-up was 11·8 years (IQR 17-26) from study entry and did not differ between countries. There were no significant differences in demographic characteristics, duration of follow-up, comorbidities, treatment number, or type of treatment between women and men, so we pooled data from both sexes for survival analysis. 51 (16%) of the cohort died during follow-up from study entry (10 years after cure). Median survival from study entry was similar for women (31 years; IQR 19-38) and men (28 years; 24-42), and about 40 years (IQR 30-48) from remission. The overall SMR for all-cause mortality was 1·61 (95% CI 1·23-2·12; p=0·0001). The SMR for circulatory disease was increased at 2·72 (1·88-3·95; p<0·0001), but deaths from cancer were not higher than expected (0·79, 0·41-1·51). Presence of diabetes, but not hypertension, was an independent risk factor for mortality (hazard ratio 2·82, 95% CI 1·29-6·17; p=0·0095). We noted a step-wise reduction in survival with increasing number of treatments. Patients cured by pituitary surgery alone had long-term survival similar to that of the general population (SMR 0·95, 95% CI 0·58-1·55) compared with those who were not (2·53, 1·82-3·53; p<0·0001). INTERPRETATION: Patients with Cushing's disease who have been in remission for more than 10 years are at increased risk of overall mortality compared with the general population, particularly from circulatory disease. However, median survival from cure is excellent at about 40 years of remission. Treatment complexity and an increased number of treatments, reflecting disease that is more difficult to control, appears to negatively affect survival. Pituitary surgery alone is the preferred treatment to secure an optimum outcome, and should be done in a centre of surgical excellence. FUNDING: None.

[Adrenal insufficiency and treatment with glucocorticosteroid]. / Binyreinsufficiens og behandling med glukokortikosteroid

Lately, it has been revealed that cortisol (hydrocortisone) secretion is lower than previously thought. Replacement doses of 10-15 mg/24 h seem sufficient in non-obese individuals. The day-night variation and in particular the fast oscillations in plasma cortisol concentration may be important for the patient's well-being. The lack of these fluctuations may explain why quality of life in some patients is unsatisfactory despite seemingly adequate substitution. It has been assumed that critical disease and stress such as major surgery require increased doses of hydrocortisone. Recently, this notion has been questioned, and in many patients with serious diseases the amount of hydrocortisone secreted is not increased. At present, there is no documentation for the benefit of high doses (100-400 mg hydrocortisone) in patients with critical disease and adrenal insufficiency.

[Long-term treatment with opioid drugs].

It is well established that morphine and other opioid drugs in both men and women exert a pronounced effect on the gonads, causing hypogonadotroph hypogonadism. The thyroid function seems unimpaired. Only a small number of studies have addressed the effects of opioids on the adrenocortical function. They strongly suggest that opioids may cause adrenocortical insufficiency - even presenting as severe and life-threatening hypoadrenalism. At present a substantial number of patients are on long-term treatment with opioids, making the above findings relevant in daily clinical practice.

Use of combined search criteria improved validity of rare disease (craniopharyngioma) diagnosis in a national registry.

OBJECTIVE: To evaluate sensitivity and validity of the Danish National Patient Registry (NPR) including relevant International Classification of Diseases, Eighth Revision (ICD-8) and International Classification of Diseases, Tenth Revision (ICD-10) codes and explore potential benefits of combining diagnosis and department codes in composite search strategies. STUDY DESIGN AND SETTING: The study period was 1985-2004. Medical records of patients identified with one or more of seven ICD-8 or ICD-10 codes from a number of registries were reviewed to confirm or reject the craniopharyngioma diagnosis. NPR sensitivity was evaluated in North Jutland County through comparison with hospital registries, the county registry, and the Danish Cancer Registry. Codes and search strategies were studied using NPR data from Denmark (population 5.2 million). RESULTS: In the North Jutland County study, the NPR identified 95% of new patients with histologically verified or probable craniopharyngioma. In the code and search strategy studies, the NPR search identified 684 patients. Records were retrieved in 607 (89%), of whom 185 (30%) had verified or probable craniopharyngioma. Searches combining "best code" and "highly specialized department" or "neurosurgery procedure" registrations improved validity considerably, whereas reducing sensitivity only modestly. CONCLUSION: The NPR identified 95% of new craniopharyngioma patients, but only 30% of cases were correct. Validity was improved by applying a modified composite search strategy.

Hyperthyroidism, exophthalmos, and goiter: historical notes on the orbitopathy.

BACKGROUND: Exophthalmos associated with goiter and/or symptoms of hyperthyroidism have been known since antiquity. It was not until around 1800 that a number of studies described this disorder in more detail. SUMMARY: For many years the nature of the disease remained unclear and it was appreciated as either a cardiac or neurological disease. There was no agreement on treatment. Surgery on the thyroid, orbit, autonomous nerve system, and pituitary has been employed. Medical treatment was introduced around World War II. Later, as a consequence of the discovery of long-acting thyroid stimulator, it became apparent that Graves-Basedow's disease was an autoimmune disease and so was the exophthalmos, though many details of the pathophysiology remain in doubt. CONCLUSIONS: This article presents a brief review of the history of the exophthalmos associated with thyroid disease.

A century of pituitary surgery: Schloffer's legacy.

Although pituitary tumors were well recognized by the end of the 20th century, very few surgeons had attempted to remove such tumors. In 1906, Hermann Schloffer at the Innsbruck University Clinic of Surgery reviewed the subject of pituitary surgery. Very little was known about the function of the pituitary, and no reports had yet been published on attempts to surgically remove pituitary neoplasms. Schloffer pointed out that ophthalmological symptoms evidently reflected mass effect of the tumor and, hence, resection of the tumor would be beneficial. He also proposed a transsphenoidal approach to the sella, although he was well aware of the risk of meningitis associated with this procedure. On March 16, 1907, Schloffer performed the first transsphenoidal operation for a pituitary adenoma. Unfortunately, the patient died 2 months later from a large residual tumor. Within a few years, several patients had undergone operation with procedures similar to the one described by Schloffer, several of whom experienced acromegaly, thus introducing neurosurgery as routine therapy for acromegaly and settling the long debate on the etiology of acromegaly.

Nonfunctioning pituitary adenoma: incidence, causes of death and quality of life in relation to pituitary function.

The incidence of clinically significant, nonfunctioning pituitary adenoma, requiring surgical treatment, has not been established. According to previous studies, both surgery type and subsequent radiotherapy may have an impact on quality of life (QOL), and some studies have shown increased cardiovascular mortality in patients with pituitary disease. We studied all patients with functionless, suprasellar pituitary adenoma who were operated on during the period 1985-1996 (N = 192; transsphenoidal surgery = 160, craniotomy = 32). QOL was evaluated from Short Form 36 and Major Depression Inventory questionnaires. Causes of death were obtained from the Danish Register of Causes of Death. Incidence was 5.6/mill/year. Postoperatively, 27% of the patients had normal pituitary function and 27% were panhypopituitary. Fifty three patients had died. Death from cardiovascular, cerebrovascular and malignant diseases was not increased. Overall, QOL was not different from QOL of an age- and sex matched background population. QOL was, however, impaired in patients who had undergone craniotomy as compared to patients undergoing transsphenoidal surgery. QOL was not reduced in hypopituitary patients or in patients receiving radiotherapy.

A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene.

Recently, various subtypes of familial hyperinsulinemic hypoglycemia with an autosomal-dominant inheritance have been etiologically characterized. In the present study, we have delineated the genetics and metabolic phenotype of a novel form of hypoglycemia in a large pedigree with an apparent autosomal-dominant transmission. After initial investigations of the proband, her mother, and a sister, the study was extended to 19 family members in three generations. Glucose tolerance was assessed by a 5-h oral glucose tolerance test (OGTT) and insulin sensitivity by euglycemic-hyperinsulinemic clamp in six affected family members and six control subjects. To identify the genetic cause of hypoglycemia, linkage analysis and mutation analysis of genomic DNA from all family members were performed. All affected family members were characterized by postprandial hypoglycemia, fasting hyperinsulinemia, and an elevated serum insulin-to-C-peptide ratio. The 5-h OGTT demonstrated hyperinsulinemic hypoglycemia, and the clamp studies showed reduced insulin sensitivity and clearance of serum insulin in affected family members compared with control subjects. Linkage analysis and subsequent mutation screening revealed a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia. The findings demonstrate the coexistence of severe postprandial hypoglycemia, insulin resistance, and impaired insulin clearance and suggest that hypoglycemia should be considered as a phenotype linked to heterozygote mutations in the insulin receptor gene.

Diabetes insipidus: historical aspects.

The contributions to our present knowledge and understanding of diabetes insipidus are briefly surveyed. Though a disease presenting with polyuria and thirst had been recognized since Antiquity, it was not until the 17. Century the distinction was made between diabetes insipidus and diabetes mellitus. At the beginning of the 20. Century almost nothing was known about the function of the pituitary. It was generally believed that diabetes insipidus was a renal disease. Two clinical observations in 1912 suggested an association between the hypophysis and diabetes insipidus. This view was supported by the recognition in 1913 that extract of the posterior lobe of the pituitary was effective in diabetes insipidus. Despite much evidence to the contrary, it was assumed that the antidiuretic hormone was produced in the intermediate lobe of the pituitary. Around 1950 it was finally established that 'the posterior lobe hormones' are in fact secreted in the hypothalamus. At the same time the antidiuretic hormone was isolated and synthesized. More recently, progress within genetics has made it possible to characterize in details other rare types of diabetes insipidus.

Increased risk of osteoporotic fractures in patients with Cushing's syndrome.

OBJECTIVE: To evaluate if fracture risk was increased in patients with Cushing's syndrome due to the increased endogenous cortisol production. DESIGN: Cohort. METHODS: A self-administered questionnaire was mailed to 125 patients with Cushing's syndrome diagnosed between 1985 and 1999 in Denmark. The response of each patient was compared with that of three age- and gender-matched control subjects randomly drawn among respondents to the same questionnaire from the background population. RESULTS: One hundred and four patients (83%) responded. The median age of the patients was 48 years (range 19-85 years). Sixty-eight had pituitary disease, 28 had adrenal disease, four had had both pituitary and adrenal surgery while four had not undergone surgery at the time of the study. The median time from diagnosis to surgery was 0.2 (range 0-3) years. Eighty-six percent were cured following surgery. There was an increased fracture risk within the last 2 years prior to diagnosis (incidence rate ratio 6.0, 95% confidence intervals (CI): 2.1-17.2). More than 2 years prior to diagnosis and following diagnosis there was no difference in fracture risk between patients and controls. The patients had more low-energy fractures than the controls (relative risk 5.4, 95% CI: 1.4-20.1). There was no difference in fracture risk between patients with adrenal or pituitary disease. CONCLUSIONS: Patients with Cushing's syndrome had an increased fracture risk in a narrow time interval before diagnosis, while no increase in fracture risk could be demonstrated after diagnosis and treatment.