Summary
Objective Untreated Cushing’s syndrome (CS) is associated with significant morbidity and mortality. However, recent operative series suggest low morbidity and mortality for CS, whereas ...population‐based surveys report elevated mortality rates. We investigated the mortality and morbidity of CS in New Zealand.
Design A nationwide retrospective survey of patients with CS between 1960 and 2005 managed at the four main endocrinology services.
Patients A total of 253 patients with CS were identified, excluding adrenal carcinoma and malignant ectopic CS.
Measurements The primary outcome was the standardized mortality ratio (SMR), comparing the observed number of deaths with the expected number for the population matched for age, sex and duration of follow‐up. Secondary outcomes were the change in prevalence of co‐morbidities at presentation and at final follow‐up.
Results The approximate prevalence and incidence of CS was 79/million and 1·8/million/y. The mean age at presentation was 39 year, and median duration of follow‐up was 6·4 year (range 0–46). Overall, 89% achieved biochemical cure at last follow‐up, with >90% achieving biochemical cure for CS from adrenal adenoma and pituitary causes. Thirty‐six patients died during follow‐up compared with 8·8 expected deaths (SMR 4·1, 95%CI 2·9–5·6). While hypertension, sexual dysfunction, myopathy and mild psychiatric illness were significantly reduced after treatment, hypertension, diabetes mellitus, moderate or major psychiatric illness, and osteoporosis were common at final follow‐up.
Conclusion CS is associated with both high mortality and a high prevalence of co‐morbidities, even when biochemical cure rates are between 80% and 90%.
Factors Influencing Mortality in Acromegaly Holdaway, Ian M; Rajasoorya, Raja C; Gamble, Greg D
The journal of clinical endocrinology and metabolism,
2004-February, Letnik:
89, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Studies of acromegaly have shown a doubling of mortality compared with the general population. With the development of new modalities of treatment, it has become important to identify prognostic ...factors relating to mortality. Between 1964 and 2000, 208 acromegalic patients were followed for a mean of 13 yr at Auckland Hospital. Treatment was by surgery or radionuclide pituitary implantation, and all except 27 patients received pituitary radiation. Over the duration of the study, 72 patients died at a mean age of 61 ± 12.8 yr. Those dying were significantly older at diagnosis, had a higher prevalence of hypertension and diabetes, and were more likely to have hypopituitarism. The observed to expected mortality ratio (O/E ratio) fell from 2.6 (95% confidence interval, 1.9–3.6) in those with last follow-up GH greater than 5 μg/liter to 2.5 (1.6–3.8), 1.6 (0.9–3), and 1.1 (0.5–2.1) for those with GH less than 5, less than 2, and less than 1 μg/liter, respectively (P < 0.001). Serum IGF-I, expressed as an sd score, was significantly associated with mortality, with O/E mortality ratios of 3.5 (95% confidence interval, 2.8–4.2) for those with an sd score greater than 2, 1.6 (0.6–2.6) for those with an sd score less than 2 (normal or low levels), and 1.0 (0.1–3) for those with an sd score less than zero. When assessed by multivariate analysis, last serum GH (P < 0.001), age, duration of symptoms before diagnosis (P < 0.03), and hypertension (P < 0.04) were independent predictors of survival. If IGF-I was substituted for GH, then survival was independently related to last IGF-I sd score (P < 0.02), indicating that GH and IGF-I act equivalently as predictors of mortality. These findings indicate that reduction of GH to less than 1 μg/liter or normalization of serum IGF-I reduces mortality to expected levels.
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.
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.
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).
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.
None.
The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations
of the dual zinc finger transcription factor, GATA3. The C-terminal zinc ...finger (ZnF2) binds DNA, whereas the N-terminal finger
(ZnF1) stabilizes this DNA binding and interacts with other zinc finger proteins, such as the Friends of GATA (FOG). We have
investigated seven HDR probands and their families for GATA3 abnormalities and have identified two nonsense mutations (Glu-228 â Stop and Arg-367 â Stop); two intragenic deletions that
result in frameshifts from codons 201 and 355 with premature terminations at codons 205 and 370, respectively; one acceptor
splice site mutation that leads to a frameshift from codon 351 and a premature termination at codon 367; and two missense
mutations (Cys-318 â Arg and Asn-320 â Lys). The functional effects of these mutations, together with a previously reported
GATA3 ZnF1 mutation and seven other engineered ZnF1 mutations, were assessed by electrophoretic mobility shift, dissociation,
yeast two-hybrid and glutathione S -transferase pull-down assays. Mutations involving GATA3 ZnF2 or adjacent basic amino acids resulted in a loss of DNA binding,
but those of ZnF1 either lead to a loss of interaction with specific FOG2 ZnFs or altered DNA-binding affinity. These findings
are consistent with the proposed three-dimensional model of ZnF1, which has separate DNA and protein binding surfaces. Thus,
our results, which expand the spectrum of HDR-associated GATA3 mutations and report the first acceptor splice site mutation, help to elucidate the molecular mechanisms that alter the function
of this zinc finger transcription factor and its role in causing this developmental anomaly.
IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular ...enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.
ObjectiveFormal studies of acromegaly have found increased mortality associated with the disorder, although reduction of serum levels of GH and IGF-I by treatment appears to improve survival. A ...meta-analysis of mortality studies in acromegaly has thus been performed to assess the effect of lowering serum GH and IGF-I on survival.Design and methodsMedline was searched for studies under ‘acromegaly’, ‘mortality’ and ‘cause of death’ (1965–2008), and of recent meetings of the US Endocrine Society were hand searched. Studies were restricted to those presenting mortality data according to serum GH and IGF-I at last follow-up, and with mortality expressed as a standardized mortality ratio (SMR).ResultsPatients with random serum GH <2.5 μg/l following treatment, mostly measured by standard RIA, had mortality close to expected levels (SMR 1.1, 95% confidence interval (CI) 0.9–1.4) compared with an SMR of 1.9 (95% CI 1.5–2.4) for those with final GH >2.5 μg/l. Similarly, a normal serum IGF-I for age and sex at last follow-up after treatment was associated with an SMR of 1.1 (95% CI 0.9–1.4) compared with an SMR of 2.5 (95% CI 1.6–4.0) for those with continued IGF-I elevation. There was a significant trend for reduced mortality in series reporting frequent use of somatostatin analogues and in studies reporting high (>70%) rates of biochemical remission after treatment.ConclusionsClinicians treating acromegalic patients should aim for random serum GH <2.5 μg/l measured by RIA (probably <1 μg/l measured by modern sensitive immunoassay) and normal serum IGF-I values, to restore the elevated mortality of the condition to normal levels.
Acquired central diabetes insipidus (CDI) often occurs abruptly after a cranial event causing hypothalamic or pituitary damage. We present a case of a patient with pre-existing and clinically ...unapparent CDI which was unmasked after renal transplantation. A 60 year old woman with end-stage renal failure due to autosomal dominant polycystic kidney disease (ADPKD) underwent renal transplantation. She was noted to be markedly polyuric and polydipsic after the transplant. A fluid deprivation test was unequivocally positive for CDI, and desmopressin treatment resulted in immediate symptom relief. Neuroimaging revealed a midline defect in the region of the hypothalamus. She had a history of an intracerebral aneurysm that had ruptured, requiring extensive neurosurgery many years previously. This case demonstrates a rare instance of pre-existing but clinically unapparent CDI unmasked by renal transplantation. It is likely that renal failure due to ADPKD disguised her CDI prior to transplantation. A previous intracerebral insult from an aneurysmal bleed is the likely cause of her vasopressin deficiency.
Three-dimensional printing of implants allows the ability to produce implants and interfaces which theoretically better mimic “normal” bone behaviour, leading to a possible reduction in stress ...shielding thus maintaining bone mineral density (BMD). This issue was not investigated in vivo using bone scan and different bearings, therefore we did a prospective study aiming to answer: 1) Is there a loss of BMD around the 3D printed trabecular titanium cup, when compared to the native hip? 2) Does liner type influence the BMD changes around the acetabulum when a 3D printed trabecular titanium cup is used?
BMD changes around the acetabulum are not influenced by the liner type, and the cup will be associated with a reduction in BMD when compared to the native hip.
This is a prospective observational study of patients receiving a primary total hip arthroplasty. A 3D printed Trabecular Titanium uncemented acetabular component was used in all cases. All patients received a ceramic femoral head, with either a ceramic or polyethylene acetabular liner. BMD measurements using DXA were performed at 6 weeks, 6,12 and 24 months after surgery to evaluate remodeling changes. The 3 acetabular regions of interest (ROI) of DeLee and Charnley were used for serial comparisons of peri-acetabular BMD. The study was powered as a non-inferiority study with the principle variables compared using a two-step repeated analysis of variance.
A total of 48 consecutive patients were included in the study, with all patients completing their 2 year follow up. There were no failures, revisions or complications within this cohort. We found no statistically significant difference in the BMD change scores between the operated and the native hip in any of the 3 ROI zones. We found no differences in BMD scores when comparing ceramic to polyethylene acetabular liners, head sizes and BMI.
This study shows a similar pattern of BMD behaviour around a 3D printed cup when compared to the contralateral native hip. We were unable to show a clinical or radiological difference between the bearing material, head size, or BMI when used with this type of acetabular component.
III; prospective comparative study.
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