| 1. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 2. |
- Burman, Pia, et al.
(författare)
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Deaths Among Adult Patients With Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality
- 2013
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:4, s. 1466-1475
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Tidskriftsartikel (refereegranskat)abstract
- Context: Patients with hypopituitarism have an increased standardized mortality rate. The basis for Objective: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism Design and Methods: All-cause and cause-specific mortality in 1286 Swedish patients with Main Outcome Measures: Standardized mortality ratios (SMR) were calculated, with stratification for Results: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence Conclusion: Two important causes of excess mortality were identified: first, adrenal crisis in response
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| 3. |
- Dalin, Frida, 1984-, et al.
(författare)
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Clinical and immunological characteristics of Autoimmune Addison's disease : a nationwide Swedish multicenter study
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 102:2, s. 379-389
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.
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| 4. |
- Espiard, Stéphanie, et al.
(författare)
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Improved Urinary Cortisol Metabolome in Addison's disease: a Prospective Trial of Dual-Release Hydrocortisone.
- 2021
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 106:3, s. 814-825
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Tidskriftsartikel (refereegranskat)abstract
- Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism.To study cortisol metabolism during DR-HC and TID-HC.Randomized, 12-week, crossover study.DC-HC and same daily dose of TID-HC in patients with primary adrenal insufficiency (n=50) versus healthy subjects (n=124) as control.Urinary corticosteroid metabolites measured by gas chromatography/mass spectrometry on 24-hour urinary collections.Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < 0.001) and reached control values (P = 0.089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol+5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < 0.05), but remained increased versus controls (P < 0.001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC versus controls (P < 0.01) but normalized with DR-HC (P = 0.358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity.The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change towards normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.
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| 5. |
- Filipsson, Helena, 1966, et al.
(författare)
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The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:10, s. 3954-61
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hypopituitary patients with untreated GH deficiency and patients on inappropriately high doses of glucocorticoid (GC) share certain clinical features. OBJECTIVE: The aim of the study was to examine the influence of GC substitution on clinical characteristics in hypopituitary patients before and after GH replacement therapy. METHOD: A total of 2424 hypopituitary patients within the KIMS (Pfizer International Metabolic Database) were grouped according to ACTH status. Comparisons were performed between subjects on hydrocortisone (HC) (n = 1186), cortisone acetate (CA) (n = 487), and prednisolone/dexamethasone (n = 52), and ACTH-sufficient patients (AS) (n = 717) before and after 1 yr of GH treatment in terms of body mass index, waist and hip circumference, blood pressure, glucose, glycosylated hemoglobin (HbA1c), serum lipids, IGF-I, and comorbidity. Hydrocortisone equivalent (HCeq) doses were calculated, and measurements were adjusted for sex and age. RESULTS: At baseline, the HC group had increased total cholesterol, triglycerides, waist circumference, and HbA1c, and the prednisolone/dexamethasone group had increased waist/hip ratio as compared with AS. After HCeq dose adjustment, the HC group retained higher HbA1c than the CA group. GC-treated patients showed a dose-related increase in serum IGF-I, body mass index, triglycerides, low-density lipoprotein cholesterol and total cholesterol levels. Subjects with HCeq doses less than 20 mg/d (n = 328) at baseline did not differ from AS in metabolic endpoints. The 1-yr metabolic response to GH was similar in all GC groups and dose categories. All new cases of diabetes (n = 12), stroke (n = 8), and myocardial infarction (n = 3) during GH treatment occurred in GC-treated subjects. CONCLUSION: HCeq doses of at least 20 mg/d in adults with hypopituitarism are associated with an unfavorable metabolic profile. CA replacement may have metabolic advantages compared with other GCs.
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| 6. |
- Hellgren, Gunnel, 1961, et al.
(författare)
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The growth hormone receptor exon 3-deleted/full-length polymorphism and response to growth hormone therapy in prepubertal idiopathic short children
- 2015
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Ingår i: Growth Hormone & IGF Research. - : Elsevier BV. - 1096-6374 .- 1532-2238. ; 25:3, s. 127-135
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The primary aim of the study was to evaluate d3-GHR as a possible cause of increased GH sensitivity in children with delayed infancy-childhood transition (DICT). The secondary aim was to investigate the impact of the GHR exon 3 deleted/full-length (d3/f1) polymorphism on GH treatment response in prepubertal children classified as having idiopathic short stature (ISS). Design: Study subjects included 167 prepubescent longitudinally followed children classified as having ISS. Children were randomized to standard-dose GH treatment (33 mu g kg(-1) day(-1)), to double-dose treatment (67 mu g kg(-1) day(-1)), or to an untreated control group. Growth and metabolic outcome were evaluated at birth (n = 166), after one year of treatment (n = 59) and at adult height (n = 145). Genotyping of the GHR d3/f1 polymorphism was performed using TaqMan SNP genotyping of tagSNP rs6873545. Results: Birth and early growth data did not reach the predetermined level of statistical significance for difference between genotypes. Growth and IGF-1 response after one year of GH treatment did not differ between genotypes. IGFBP-3(SDS) was higher in untreated d3-GHR carriers than in untreated fl/fl individuals, whereas there was insufficient evidence for higher IGFBP-3(SDS) in treated d3-GHR carriers. Genotype did not explain the growth response to treatment, and no differences in height(SDS), height gain, or difference in height to midparental height(SDS) between genotype groups were found at adult height. Conclusion: The common GHR d3/fl polymorphism is probably not a cause of DICT in children with ISS, and our results do not suggest that the d3-GHR genotype is associated with increased sensitivity to GH in children with ISS.
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| 7. |
- Holmer, Helene, et al.
(författare)
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Nonfatal stroke, cardiac disease, and diabetes mellitus in hypopituitary patients on hormone replacement including growth hormone
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 92:9, s. 3560-3567
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Tidskriftsartikel (refereegranskat)abstract
- Context: The impact of long-term GH replacement on cerebrovascular and cardiovascular diseases and diabetes mellitus in hypopituitary patients is unknown. Objective: The incidence of nonfatal stroke and cardiac events, and prevalence of type 2 diabetes mellitus ( T2D) and cardioprotective medication were compared between cohorts of GH-deficient (GHD) patients and population controls. Design and Participants: The incidence of nonfatal stroke and cardiac events was estimated retrospectively from questionnaires in 750 GHD patients and 2314 matched population controls. A prevalence of T2D and cardioprotective medication was recorded at the distribution of questionnaires. Time since first pituitary deficiency to start of GH therapy was 4 and 2 yr, and time on GH therapy was 6 yr for GHD women and men, respectively. Results: Lifelong incidence of nonfatal stroke was tripled in GHD women and doubled in GHD men, but a decline was seen in both genders during periods after first pituitary hormone deficiency and GHD, during which most patients had GH therapy. The lifelong incidence of nonfatal cardiac events declined in GHD men during first pituitary hormone deficiency and GHD periods. GHD women had a higher prevalence of T2D and lipid-lowering medication, whereas GHD men had a higher prevalence of antihypertensive medication. Conclusions: The declined risks of nonfatal stroke in both genders and of nonfatal cardiac events in GHD men during periods on GH replacement may be caused by prescription of cardioprotective drugs and 6-yr GH replacement. GHD women had an increased prevalence of T2D, partly attributed to higher body mass index and lower physical activity.
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| 8. |
- Johannsson, Gudmundur, 1960, et al.
(författare)
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Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy.
- 2015
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Ingår i: Clinical endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 82:1
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoid replacement therapy in patients with adrenal insufficiency (AI), whether primary (Addison's disease) or secondary (due to hypopituitarism), has been established for some 50 years. The current standard treatment regimen involves twice- or thrice-daily dosing with a glucocorticoid, most commonly oral hydrocortisone. Based on previous small-scale studies and clinical perception, life expectancy with conventional glucocorticoid replacement therapy has been considered normal, with a low incidence of adverse events. Data from the past 10-15 years, however, have shown that morbidity remains high and life expectancy is reduced. The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress-related events. This is thought to reflect a failure of treatment to replicate the natural circadian rhythm of cortisol release, together with a failure to identify and deliver individualized cortisol exposure and to manage patients adequately when increased doses are required. The resulting over- or under-treatment may result in Cushing-like symptoms or adrenal crisis, respectively. This review summarizes the morbidity and mortality seen in patients receiving the current standard of care for AI and suggests areas for improvement in glucocorticoid replacement therapy.
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| 9. |
- Johannsson, Gudmundur, 1960, et al.
(författare)
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Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency : a prospective randomised trial of a novel hydrocortisone dual-release formulation
- 2012
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 97:2, s. 473-481
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Tidskriftsartikel (refereegranskat)abstract
- Context: Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile.Objective: The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets.Design and Setting: We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers.Patients: The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM).Intervention: The same daily dose of hydrocortisone was administered as OD dual-release or TID.Main Outcome Measure: We evaluated cortisol pharmacokinetics.Results: Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004).Conclusion: The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.
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| 10. |
- Johannsson, Gudmundur, 1960, et al.
(författare)
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Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study.
- 2009
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X .- 0804-4643. ; 161:1, s. 119-30
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Endogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to develop a once daily oral dual-release formulation for cortisol replacement therapy that mimics the diurnal variation in the plasma cortisol profile. OBJECTIVE: To determine single-dose plasma pharmacokinetics and dose-proportionality of oral 5 and 20 mg dual-release hydrocortisone tablets in healthy volunteers. In addition, the effect of food intake was investigated for the 20 mg dose. DESIGN: A randomised, controlled, two-way cross-over, double-blind, phase I study of oral hydrocortisone (modified (dual) release; 5 and 20 mg) with an open food-interaction arm. METHODS: The single dose pharmacokinetic studies were performed with betamethasone suppression. The two first study days were blinded and randomised between morning administration of 5 and 20 mg tablet in a fasting state. The third day was open with a 20 mg tablet taken 30 min after a high-calorie, high-fat meal. The plasma samples were assayed using both a validated LC-MS/MS and an immunoassay. The plasma pharmacokinetic variables were calculated using non-compartmental data analysis. RESULTS: The time to reach a clinically significant plasma concentration of cortisol (>200 nmol/l) was within 20 min and a mean peak of 431 (s.d. 126) nmol/l was obtained within 50 min after administration of the 20 mg tablet. Plasma cortisol levels remained above 200 nmol/l for around 6 h thereafter and all plasma concentrations 18-24 h after intake were below 50 nmol/l. In the fed state the time to reach 200 nmol/l was delayed by 28 and 9 min based on LC-MS/MS and immunoassay, respectively. The 5 and 20 mg tablets produced an increase in plasma exposure of cortisol that was not fully dose proportional. CONCLUSION: The dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.
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