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Frontiers in Endocrinology 2023X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.
Topics: Adult; Humans; Male; Female; Child; Adrenoleukodystrophy; ATP-Binding Cassette Transporters; Addison Disease; Fatty Acids; Adrenal Cortex; Glucocorticoids
PubMed: 38034003
DOI: 10.3389/fendo.2023.1309053 -
Frontiers in Endocrinology 2023The adrenal glands are small endocrine glands located on top of each kidney, producing hormones regulating important functions in our body like metabolism and stress.... (Review)
Review
The adrenal glands are small endocrine glands located on top of each kidney, producing hormones regulating important functions in our body like metabolism and stress. There are several underlying causes for adrenal insufficiency, where an autoimmune attack by the immune system is the most common cause. A number of genes are known to confer early onset adrenal disease in monogenic inheritance patterns, usually genetic encoding enzymes of adrenal steroidogenesis. Autoimmune primary adrenal insufficiency is usually a polygenic disease where our information recently has increased due to genome association studies. In this review, we go through the physiology of the adrenals before explaining the different reasons for adrenal insufficiency with a particular focus on autoimmune primary adrenal insufficiency. We will give a clinical overview including diagnosis and current treatment, before giving an overview of the genetic causes including monogenetic reasons for adrenal insufficiency and the polygenic background and inheritance pattern in autoimmune adrenal insufficiency. We will then look at the autoimmune mechanisms underlying autoimmune adrenal insufficiency and how autoantibodies are important for diagnosis. We end with a discussion on how to move the field forward emphasizing on the clinical workup, early identification, and potential targeted treatment of autoimmune PAI.
Topics: Humans; Addison Disease; Adrenal Insufficiency; Adrenal Glands; Autoantibodies; Kidney
PubMed: 38027140
DOI: 10.3389/fendo.2023.1285901 -
Journal of Nephrology Apr 2024
Topics: Humans; Female; Pregnancy; Renal Insufficiency, Chronic; Disease Progression; Pregnancy Complications; Predictive Value of Tests; Reproducibility of Results; Research Design; Risk Factors
PubMed: 37989974
DOI: 10.1007/s40620-023-01788-5 -
Journal of Cardiovascular Magnetic... Nov 2023Ventricular dyssynchrony and its relationship to clinical outcomes is not well characterized in patients following Fontan palliation.
BACKGROUND
Ventricular dyssynchrony and its relationship to clinical outcomes is not well characterized in patients following Fontan palliation.
METHODS
Single-center retrospective analysis of cardiac magnetic resonance (CMR) imaging of patients with a Fontan circulation and an age-matched healthy comparison cohort as controls. Feature tracking was performed on all slices of a ventricular short-axis cine stack. Circumferential and radial strain, strain rate, and displacement were measured; and multiple dyssynchrony metrics were calculated based on timing of these measurements (including standard deviation of time-to-peak, maximum opposing wall delay, and maximum base-to-apex delay). Primary endpoint was a composite measure including time to death, heart transplant or heart transplant listing (D/HTx).
RESULTS
A total of 503 cases (15 y; IQR 10, 21) and 42 controls (16 y; IQR 11, 20) were analyzed. Compared to controls, Fontan patients had increased dyssynchrony metrics, longer QRS duration, larger ventricular volumes, and worse systolic function. Dyssynchrony metrics were higher in patients with right ventricular (RV) or mixed morphology compared to those with LV morphology. At median follow-up of 4.3 years, 11% had D/HTx. Multiple risk factors for D/HTx were identified, including RV morphology, ventricular dilation, dysfunction, QRS prolongation, and dyssynchrony. Ventricular dilation and RV morphology were independently associated with D/HTx.
CONCLUSIONS
Compared to control LVs, single right and mixed morphology ventricles in the Fontan circulation exhibit a higher degree of mechanical dyssynchrony as evaluated by CMR-FT. Dyssynchrony indices correlate with ventricular size and function and are associated with death or need for heart transplantation. These data add to the growing understanding regarding factors that can be used to risk-stratify patients with the Fontan circulation.
Topics: Humans; Fontan Procedure; Retrospective Studies; Predictive Value of Tests; Heart Ventricles; Heart
PubMed: 37986080
DOI: 10.1186/s12968-023-00984-3 -
Health Technology Assessment... Nov 2023Guided self-help has been shown to be effective for other mental conditions and, if effective for post-traumatic stress disorder, would offer a time-efficient and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Guided self-help has been shown to be effective for other mental conditions and, if effective for post-traumatic stress disorder, would offer a time-efficient and accessible treatment option, with the potential to reduce waiting times and costs.
OBJECTIVE
To determine if trauma-focused guided self-help is non-inferior to individual, face-to-face cognitive-behavioural therapy with a trauma focus for mild to moderate post-traumatic stress disorder to a single traumatic event.
DESIGN
Multicentre pragmatic randomised controlled non-inferiority trial with economic evaluation to determine cost-effectiveness and nested process evaluation to assess fidelity and adherence, dose and factors that influence outcome (including context, acceptability, facilitators and barriers, measured qualitatively). Participants were randomised in a 1 : 1 ratio. The primary analysis was intention to treat using multilevel analysis of covariance.
SETTING
Primary and secondary mental health settings across the United Kingdom's National Health Service.
PARTICIPANTS
One hundred and ninety-six adults with a primary diagnosis of mild to moderate post-traumatic stress disorder were randomised with 82% retention at 16 weeks and 71% at 52 weeks. Nineteen participants and ten therapists were interviewed for the process evaluation.
INTERVENTIONS
Up to 12 face-to-face, manualised, individual cognitive-behavioural therapy with a trauma focus sessions, each lasting 60-90 minutes, or to guided self-help using , an eight-step online guided self-help programme based on cognitive-behavioural therapy with a trauma focus, with up to five face-to-face meetings of up to 3 hours in total and four brief telephone calls or e-mail contacts between sessions.
MAIN OUTCOME MEASURES
Primary outcome: the Clinician-Administered PTSD Scale for , Fifth Edition, at 16 weeks post-randomisation. Secondary outcomes: included severity of post-traumatic stress disorder symptoms at 52 weeks, and functioning, symptoms of depression, symptoms of anxiety, alcohol use and perceived social support at both 16 and 52 weeks post-randomisation. Those assessing outcomes were blinded to group assignment.
RESULTS
Non-inferiority was demonstrated at the primary end point of 16 weeks on the Clinician-Administered PTSD Scale for , Fifth Edition [mean difference 1.01 (one-sided 95% CI -∞ to 3.90, non-inferiority = 0.012)]. Clinician-Administered PTSD Scale for , Fifth Edition, score improvements of over 60% in both groups were maintained at 52 weeks but the non-inferiority results were inconclusive in favour of cognitive-behavioural therapy with a trauma focus at this timepoint [mean difference 3.20 (one-sided 95% confidence interval -∞ to 6.00, non-inferiority = 0.15)]. Guided self-help using was not shown to be more cost-effective than face-to-face cognitive-behavioural therapy with a trauma focus although there was no significant difference in accruing quality-adjusted life-years, incremental quality-adjusted life-years -0.04 (95% confidence interval -0.10 to 0.01) and guided self-help using was significantly cheaper to deliver [£277 (95% confidence interval £253 to £301) vs. £729 (95% CI £671 to £788)]. Guided self-help using appeared to be acceptable and well tolerated by participants. No important adverse events or side effects were identified.
LIMITATIONS
The results are not generalisable to people with post-traumatic stress disorder to more than one traumatic event.
CONCLUSIONS
Guided self-help using for mild to moderate post-traumatic stress disorder to a single traumatic event appears to be non-inferior to individual face-to-face cognitive-behavioural therapy with a trauma focus and the results suggest it should be considered a first-line treatment for people with this condition.
FUTURE WORK
Work is now needed to determine how best to effectively disseminate and implement guided self-help using at scale.
TRIAL REGISTRATION
This trial is registered as ISRCTN13697710.
FUNDING
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/97) and is published in full in ; Vol. 27, No. 26. See the NIHR Funding and Awards website for further award information.
Topics: Adult; Humans; Stress Disorders, Post-Traumatic; State Medicine; Anxiety Disorders; Anxiety; Cognitive Behavioral Therapy
PubMed: 37982902
DOI: 10.3310/YTQW8336 -
Stem Cell Research Dec 2023X-linked adrenoleukodystrophy (ALD) is a rare peroxisome disease with phenotypic heterogeneity. There is a lack of suitable in vitro models to study its pathogenesis. We...
X-linked adrenoleukodystrophy (ALD) is a rare peroxisome disease with phenotypic heterogeneity. There is a lack of suitable in vitro models to study its pathogenesis. We established two strains of iPSCs from skin fibroblasts of patients with childhood cerebral ALD and Addison's disease, respectively. CytoTune™2.0 Sendai reprogramming kit was used. The iPSC lines showed typical stem cell morphology, normal karyotype, and carrying ABCD1 variation. The iPSC lines express pluripotency markers, and have the capacity to differentiate into three germ layers. iPSCs can be used as an alternative cell source for ALD in vitro model to study its pathogenesis and therapeutic strategies.
Topics: Humans; Child; Induced Pluripotent Stem Cells; Adrenoleukodystrophy; Cell Differentiation; Fibroblasts
PubMed: 37948838
DOI: 10.1016/j.scr.2023.103243 -
Journal of Veterinary Internal Medicine 2024An 18-month-old spayed female domestic short haired cat was presented for poor appetite, lethargy, exaggerated swallowing, and regurgitation 2 weeks after endoscopic...
CASE DESCRIPTION
An 18-month-old spayed female domestic short haired cat was presented for poor appetite, lethargy, exaggerated swallowing, and regurgitation 2 weeks after endoscopic retrieval of gastric foreign material.
CLINICAL FINDINGS
The cat was quiet with tacky mucous membranes on physical examination. Point-of-care blood testing identified mild azotemia, moderate hypercalcemia, and a sodium-to-potassium ratio of 26. An ultrasound examination the next day identified moderate to marked bilateral adrenomegaly. Cytology of a fine needle aspirate of the adrenal glands was consistent with necrosis and associated inflammation. Hypoadrenocorticism was diagnosed by a confirmatory adrenocorticotropic hormone stimulation test.
TREATMENT AND OUTCOME
The cat normalized both clinically and biochemically after treatment with prednisolone and desoxycorticosterone pivalate.
CLINICAL RELEVANCE
Acute adrenal necrosis has been well documented in human medicine after anesthetic events. To our knowledge, hypoadrenocorticism caused by cytologically confirmed acute adrenal necrosis has not been previously reported in dogs and cats.
Topics: Humans; Cats; Female; Animals; Dogs; Cat Diseases; Dog Diseases; Adrenal Insufficiency; Prednisolone; Hypercalcemia
PubMed: 37945312
DOI: 10.1111/jvim.16926 -
Case Reports in Endocrinology 2023A subset of patients with differentiated thyroid carcinoma develop radioiodine refractory (RAIR) incurable disease, which typically has a poor prognosis. The...
A subset of patients with differentiated thyroid carcinoma develop radioiodine refractory (RAIR) incurable disease, which typically has a poor prognosis. The multitargeted tyrosine kinase inhibitor lenvatinib has demonstrated significant improvements in progression-free survival in RAIR thyroid cancers compared to placebos. However, in the phase III SELECT trial of the drug in thyroid cancer, 5.4% of patients on lenvatinib experienced arterial thromboembolic events, with 2.7% experiencing severe grade ≥3 toxicities associated with arterial vascular events. This case study reports a patient with metastatic poorly differentiated follicular thyroid cancer who developed significant obstructive coronary artery disease following initiation of lenvatinib treatment, despite no predisposing cardiovascular risk factors apart from a remote smoking history. The possibility of developing coronary or peripheral artery disease should be considered in patients who are on targeted therapies, such as lenvatinib, even in the absence of traditional cardiovascular risk factors. In addition, baseline cardiac risk assessment and early treatment should be pursued to minimize interruptions to potentially lifesaving cancer therapy.
PubMed: 37941892
DOI: 10.1155/2023/8841696 -
Hormone and Metabolic Research =... Feb 2024Immunological abnormalities, the resulting endocrinopathies, and their treatments may impact bone health and 25-hydroxyvitamin D (25-OHD) in patients with autoimmune...
Immunological abnormalities, the resulting endocrinopathies, and their treatments may impact bone health and 25-hydroxyvitamin D (25-OHD) in patients with autoimmune polyglandular syndromes (APS). Several etiologies contribute to increased risk for low bone mineral density (BMD), including vitamin D deficiency. This study evaluated the vitamin D level and BMD of patients with APS. We performed a cross-sectional study on 44 patients with APS and 55 age and gender-matched control subjects. Among patients with APS, 14 were classified as APS-2 [Addison's disease (AD)+autoimmune thyroid disease (ATD) and/or type 1 diabetes(T1D)]. In contrast, the other 30 were APS-3 (ATD+T1D+other autoimmune diseases). Serum samples were analyzed for vitamin D levels. The lumbar spine and femoral neck BMD were measured by dual X-ray absorptiometry. Z-scores were obtained by comparison with age- and gender-matched average values (both patients and controls). The accepted normal levels were Z-score>-1 and 25-OHD>30 ng/ml. Patients with APS showed 25-OHD levels and BMD significantly lower than healthy controls (p<0.001 and p<0.05, respectively). The highest prevalence of abnormal BMD was observed in the APS-2 subgroup (13 out of 14 patients, 92.6%). Identifying and treating vitamin D deficiency and low BMD is critical in APS patients. The fact that the significant endocrine component of APS-2 is AD, and these patients receive chronic long-term glucocorticoid therapy can be shown as the reason for this result. However, more extensive prospective controlled studies are needed to confirm these findings.
Topics: Humans; Bone Density; Diabetes Mellitus, Type 1; Cross-Sectional Studies; Prospective Studies; Tertiary Care Centers; Vitamin D; Vitamin D Deficiency; Absorptiometry, Photon; Bone Diseases, Metabolic; Vitamins
PubMed: 37931915
DOI: 10.1055/a-2205-2100 -
Free Neuropathology Jan 2023The history of adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN) and other peroxisomal diseases is exemplary for the stunning progress of scientific medicine... (Review)
Review
The history of adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN) and other peroxisomal diseases is exemplary for the stunning progress of scientific medicine within the past 50 years. Like many breakthroughs in medicine, the detailed analysis of patients' pathologically affected tissues was instrumental, resulting in stepwise systematic clarification of what had remained enigmatic until the 1970s. This flashback paper is a recollection of the first neuropathological description of a slowly evolving clinical phenotype, spastic paraparesis with adrenal insufficiency, in a young adult by Budka et al. 1976 [3], using virtual microscopy of the original histologic slides. The clinico-pathological presentation derives from the classical cerebral ALD phenotype in boys, where electron microscopy demonstrated the underlying pathological hallmark of characteristic lipid inclusions shared by both phenotypes. Our report allowed the delineation of a new disease type almost simultaneously described in more cases as AMN by Griffin et al. 1977 [4] and Schaumburg et al. 1977 [11]. Moreover, our report indicated clinical heterogeneity in the ALD disease group that, as shown later, extends further to females, to Addison-only, and even to asymptomatic subjects. The gene underlying ALD was discovered in 1993 as a defect in the gene. Yet, it has hitherto remained unclear how the gene defect causes the strikingly broad and unpredictable phenotypic spectrum of ALD/AMN.
PubMed: 37915358
DOI: 10.17879/freeneuropathology-2023-5115