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This review examines the prevalence, aetiology, pathophysiology, prognostic value, and investigation of dysnatraemia in hospitalised COVID-19 patients, taking into account all relevant studies published in PubMed and Cochrane Library studies until March 2021. Hyponatraemia is commonly observed in patients with bacterial pneumonia and is an independent predictor for excess mortality and morbidity. However, it remains unknown whether this association applies to coronavirus disease-2019 (COVID-19). Several studies reported a 20-35% prevalence for hyponatraemia and 2-5% for hypernatraemia in patients admitted with COVID-19. In addition, hyponatraemia on admission was a risk factor for progression to severe disease, being associated with an increased likelihood for the need for invasive mechanical ventilation, with an odds ratio (OR) of 1.83-3.30. Hyponatraemia seems to be an independent risk factor for mortality, with an OR of 1.40-1.50 compared to normonatraemia, while hypernatraemia is related to even worse outcomes than hyponatraemia. Furthermore, preliminary data show an inverse association between serum sodium and interleukin-6 levels, suggesting that hyponatraemia might be used as a surrogate marker for the risk of a cytokine storm and the need for treatment with interleukin antagonists. In conclusion, dysnatraemia is common and carries a poor prognosis in COVID-19 patients, indicating that it may play a future role in risk stratification and individualising therapy.
Assuntos
COVID-19 , Hipernatremia , Hiponatremia , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/terapia , Comorbidade , Hospitalização/estatística & dados numéricos , Humanos , Hipernatremia/diagnóstico , Hipernatremia/epidemiologia , Hipernatremia/etiologia , Hipernatremia/terapia , Hiponatremia/diagnóstico , Hiponatremia/epidemiologia , Hiponatremia/etiologia , Hiponatremia/terapia , Pandemias , Valor Preditivo dos Testes , Prevalência , Prognóstico , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Cushing's disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing's syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70-100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised.
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Síndrome de Cushing , Hipersecreção Hipofisária de ACTH , Neoplasias Hipofisárias , Adulto , Criança , Síndrome de Cushing/etiologia , Humanos , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/epidemiologia , Hipersecreção Hipofisária de ACTH/etiologia , Hipófise/cirurgia , Neoplasias Hipofisárias/cirurgia , Resultado do TratamentoRESUMO
The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.
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DESIGN: Patients with Pendred syndrome have genotypic and phenotypic variability, leading to challenges in definitive diagnosis. Deaf children with enlarged vestibular aqueducts are often subjected to repeated investigations when tests for mutations in SLC26A4 are abnormal. This study provides genotype and phenotype information from patients with suspected Pendred syndrome referred to a single clinical endocrinology unit. METHODS: A retrospective analysis of 50 patients with suspected Pendred syndrome to investigate the correlation between genetic, perchlorate discharge test (PDT) and endocrine status. RESULTS: Eight patients with monoallelic SLC26A4 mutations had normal PDT. Of the 33 patients with biallelic mutations, ten of 12 patients with >30% discharge developed hypothyroidism. In our cohort, c.626G>T and c.3-2A>G result in milder clinical presentations with lower median perchlorate discharge of 9.3% (interquartile range 4-15%) compared with 40% (interquartile range 21-60%) for the remaining mutations. Eight novel mutations were detected. All patients with PDT <30% remained euthyroid to date, although the majority are still under the age of 30. There was a significant correlation between PDT and goitre size (R=0.61, P=0.0009) and the age of onset of hypothyroidism (R=-0.62, P=0.0297). In our population, the hazard of becoming hypothyroid increased by 7% per percentage point increase in PDT (P<0.001). CONCLUSION: There is a correlation between SLC26A4 genotype and thyroid phenotype. If results hold true for larger patient numbers and longer follow-up, then for patients with monoallelic mutations, PDT could be unnecessary. Patients with biallelic mutations and PDT discharge >30% have a high risk of developing goitre and hypothyroidism, and should have lifelong monitoring.
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Genótipo , Bócio Nodular/diagnóstico , Bócio Nodular/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Fenótipo , Encaminhamento e Consulta , Adolescente , Adulto , Estudos de Coortes , Técnicas de Diagnóstico Endócrino , Feminino , Bócio Nodular/sangue , Perda Auditiva Neurossensorial/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Pheochromocytomas and paragangliomas (PPGLs) are rare catecholamine-secreting tumors which arise from the adrenal glands or sympathetic neuronal tissue. Malignant transformation of these tumors occurs in a significant proportion and may therefore lower overall survival rates. In patients with PPGLs it is impossible to identify malignant disease without the presence of metastatic disease, something which can occur as long as 20 years after initial surgery. Early identification of malignant disease would necessitate a more aggressive treatment approach, something which may result in better disease outcome. We have therefore reviewed possible predictors of malignancy and current developments in order to help clinicians to swiftly assess malignant potential in patients with PPGLs. Currently, there is no absolute marker which can objectively reflect malignant potential. Tumor size is the most reliable predictor and should therefore be used as the baseline characteristic. The combination of various clinical markers (extra-adrenal disease and post-operative hypertension), biochemical markers (high dopamine, high norepinephrine and epinephrine to total catecholamine ratio) and/or histological markers (SNAIL, microRNAs and/or microarray results) can raise or lower the suspicion of malignancy. Furthermore, we discuss how clinical markers may affect biochemical results linked to malignancy, how biochemical results may distinguish hereditary syndromes, the role of imaging in determining malignant potential and tumor detection, and recent results of proposed histological markers.
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Neoplasias das Glândulas Suprarrenais/patologia , Transformação Celular Neoplásica/patologia , Paraganglioma Extrassuprarrenal/patologia , Feocromocitoma/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias das Glândulas Suprarrenais/metabolismo , Doenças do Sistema Nervoso Autônomo/patologia , Biomarcadores Tumorais/classificação , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/metabolismo , Humanos , Paraganglioma Extrassuprarrenal/metabolismo , Patologia Molecular , Feocromocitoma/metabolismo , Lesões Pré-Cancerosas/metabolismo , Valor Preditivo dos TestesRESUMO
BACKGROUND: Aggressive pituitary tumours are associated with substantial morbidity and mortality. Treatment options are often limited, and chemotherapy has been reserved as salvage therapy although historically results have often been disappointing. However, temozolomide, an oral alkylating agent, has recently demonstrated significant activity against these tumours. A DNA repair protein, 06-methylguanine-DNA methyltransferase (MGMT) has been suggested as a biomarker to predict response to temozolomide in pituitary tumours. MATERIALS AND METHODS: This paper will review the current literature on temozolomide and pituitary tumours and discuss the recent controversy surrounding the value of determining the MGMT status in this tumour group. A PubMed search was performed to retrieve articles, using the terms 'pituitary tumour' and 'temozolomide'. RESULTS: Overall, 24/40 (60%) of the published cases demonstrated a response to temozolomide therapy. The highest response rates were seen amongst prolactinomas (73%) and ACTH-secreting tumours (60%), whilst nonfunctioning pituitary tumours exhibit lower response rates (40%). Responsivity is typically evident in the first 3 months of therapy and may be dramatic and sustained. Low MGMT expression, as determined by immunohistochemistry, is associated with a high response rate (76%), whilst high MGMT expression has not been associated with responses. MGMT promoter methylation does not correlate with temozolomide response. CONCLUSIONS: Temozolomide is the first chemotherapeutic agent to show substantial response rates in aggressive pituitary tumours. MGMT immunohistochemistry, but not MGMT methylation analysis, shows promise as a predictive tool. Prospective clinical trials are now necessary to more accurately determine the efficacy of this agent in this patient group.
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Adenoma/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico , Carcinossarcoma/tratamento farmacológico , Dacarbazina/análogos & derivados , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Neoplasias Hipofisárias/tratamento farmacológico , Adenoma/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinossarcoma/metabolismo , Dacarbazina/uso terapêutico , Humanos , Neoplasias Hipofisárias/metabolismo , TemozolomidaRESUMO
OBJECTIVE: Mitotane treatment in adrenocortical carcinoma (ACC) results in unreliable measurement of serum total cortisol (TC) levels because of an elevation in corticosteroid-binding globulin (CBG). DESIGN: The use of a newly-developed serum-free cortisol (FC) assay was assessed to investigate the characteristics of a more valid measure of cortisol status. PATIENTS: Sixty-two serum samples from patients with ACC treated with mitotane were studied. Different subgroups were studied according to mitotane levels (<14, 14-20 and >20 mg/dl), hydrocortisone replacement treatment, presence of Cushing's syndrome (CS) and adrenocorticotrophin (ACTH) levels. MEASUREMENTS: Serum FC was measured using a newly-developed assay, TC, CBG and plasma ACTH using conventional laboratory kits; TC-to-CBG (Free cortisol index, FCI, nmol/mg) and TC-to-FC (TFR) ratios were calculated. RESULTS: CBG levels were elevated and positively correlated to mitotane levels. FC was positively related to TC and FCI in nearly all subgroups studied. Plasma ACTH was negatively related to parameters of cortisol levels in the total samples studied. In the 'target' subgroup with normal ACTH levels and mitotane levels 14-20 mg/dl, no correlation of plasma ACTH with any parameter studied was seen, and FC suggested over-replacement with hydrocortisone treatment in the subgroup with CS. CONCLUSIONS: FC measurement may offer additional information in the follow-up of patients on mitotane, especially when there is a history of CS which invalidates the use of acute changes in plasma ACTH as a parameter of hydrocortisone replacement. These preliminary data suggest that it may prove useful as a biochemical marker when TC or FCI are invalidated by mitotane treatment or plasma ACTH is suppressed by hypercortisolaemia. Larger studies are needed to substantiate the clinical utility of FC measurement in specific groups of patients.
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Neoplasias do Córtex Suprarrenal/sangue , Carcinoma Adrenocortical/sangue , Antineoplásicos Hormonais/uso terapêutico , Hidrocortisona/sangue , Mitotano/uso terapêutico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Hormônio Adrenocorticotrópico/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
OBJECTIVE: Germline mutations in the MEN1 gene predispose to the multiple endocrine neoplasia (MEN1) syndrome; however, approximately 10-20% of patients with MEN1 do not have a detectable MEN1 mutation. A rat strain with multiple endocrine tumours, a phenotypic overlap of both MEN1 and MEN2, has been reported to have a homozygous germline p27 (CDKN1B) mutation. Recently, two MEN1 mutation-negative MEN1 syndrome patients have been identified to harbour a germline CDKN1B mutation. The recently identified gene AIP can also cause familial isolated pituitary adenoma, but no other specific tumour is associated with this syndrome. The objective of this study was to evaluate the possible contribution of CDKN1B and AIP germline mutations in a cohort of MEN1 mutation-negative MEN1 syndrome patients. PATIENTS: Eighteen sporadic and three familial cases of MEN1 mutation-negative MEN1 syndrome were studied (18 pituitary adenomas, 12 hyperparathyroidism, 10 neuroendocrine tumours including 2 ACTH-secreting lesions and one adrenal nodular hyperplasia). Clinical data and genomic DNA were analysed for mutations in the CDKN1B and AIP genes. RESULTS: There were no mutations in the coding region or exon/intron junction of the CDKN1B and AIP genes in any patient. Although we have a limited number of patients in our cohort, our data is consistent with others in the literature suggesting that CDKN1B and AIP mutations are extremely rare in MEN1 syndrome. CONCLUSION: Our results suggest that mutations in the CDKN1B and AIP genes are relatively uncommon in MEN1 mutation-negative MEN1 syndrome patients.