RESUMO
A total of 1 out of 10 patients with primary hyperparathyroidism (PHP) presents an underlying genetic form, such as multiple endocrine neoplasia types 1, 2A, etc., as well as hyperparathyroidism-jaw tumour syndrome (HJT). We aimed to summarise the recent data, thus raising more awareness regarding HJT, from the clinical perspective of PHP in association with the challenges and pitfalls of CDC73 genetic testing and parafibromin staining. This narrative review included a sample-focused analysis from the past decade according to a PubMed search. We identified 17 original human studies (≥4 patients per article). The mean age at disease onset was between 20.8 and 39.5 years, while the largest study found that 71% of patients had HJT recognised before the age of 30. Males and females seemed to be equally affected, in contrast with sporadic PHP. PHP represented the central manifestation of HJT, occurring as the first manifestation in up to 85% of HJT cases. A biochemistry panel found a mean serum calcium level above the level of 12 mg/dL in PHP. PTH was elevated in HJT as well, with average values of at least 236.6 pg/mL. The most frequent pathological type in PHP was a parathyroid adenoma, but the incidence of a parathyroid carcinoma was much higher than in non-HJT cases (15% of all parathyroid tumours), with the diagnosis being established between the age of 15 and 37.5. In some families up to 85% of carriers suffered from a parathyroid carcinoma thus indicating that certain CDC73 pathogenic variants may harbour a higher risk. An important issue in HJT was represented by the parafibromin profile in the parathyroid tumours since in HJT both parathyroid adenomas and carcinomas might display a deficient immunoreactivity. Another frequent manifestation in HJT was ossifying fibromas of the jaw (affecting 5.4% to 50% of patients; the largest study found a prevalence of 15.4%). HJT was associated with a wide variety of kidney lesion (mostly: kidney cysts, with a prevalence of up to 75%, and renal tumours involved in 19% of patients). The risk of uterine lesions seemed increased in HJT, especially with concern to leiomyomas, adenofibromas, and adenomyosis. The underlying pathogenic mechanisms and the involvement of CDC73 pathogenic variants and parafibromin expression are yet to be explored. Currently, the heterogeneous expression of parafibromin status and, the wide spectrum of CDC73 mutations including the variety of clinical presentations in HJT, make it difficult to predict the phenotype based on the genotype. The central role of HJT-PHP is, however, the main clinical element, while the elevated risk of parathyroid carcinoma requires a special awareness.
Assuntos
Adenoma , Fibroma , Hiperparatireoidismo , Neoplasias Maxilomandibulares , Neoplasias das Paratireoides , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/diagnóstico , Neoplasias Maxilomandibulares/genética , Hiperparatireoidismo/genética , Hiperparatireoidismo/patologia , Fibroma/genética , Fatores de Transcrição , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
We aimed to provide an in-depth analysis with respect to three turning points in pancreas involvement in primary hyperparathyroidism (PHP): hypercalcemia-induced pancreatitis (HCa-P), MEN1 (multiple endocrine neoplasia)-related neuroendocrine tumors (NETs), and insulin resistance (IR). This was a comprehensive review conducted via a PubMed search between January 2020 and January 2024. HCa-P (n = 9 studies, N = 1375) involved as a starting point parathyroid NETs (n = 7) or pancreatitis (n = 2, N = 167). Case report-focused analysis (N = 27) showed five cases of pregnancy PHP-HCa-P and three reports of parathyroid carcinoma (female/male ratio of 2/1, ages of 34 in women, men of 56). MEN1-NET studies (n = 7) included MEN1-related insulinomas (n = 2) or MEN1-associated PHP (n = 2) or analyses of genetic profile (n = 3), for a total of 877 MEN1 subjects. In MEN1 insulinomas (N = 77), the rate of associated PHP was 78%. Recurrence after parathyroidectomy (N = 585 with PHP) was higher after less-than-subtotal versus subtotal parathyroidectomy (68% versus 45%, p < 0.001); re-do surgery was 26% depending on surgery for pancreatic NETs (found in 82% of PHP patients). MEN1 pathogenic variants in exon 10 represented an independent risk factor for PHP recurrence. A single pediatric study in MEN1 (N = 80) revealed the following: a PHP rate of 80% and pancreatic NET rate of 35% and 35 underlying germline MEN1 pathogenic variants (and 3/35 of them were newly detected). The co-occurrence of genetic anomalies included the following: CDC73 gene variant, glucokinase regulatory protein gene pathogenic variant (c.151C>T, p.Arg51*), and CAH-X syndrome. IR/metabolic feature-focused analysis identified (n = 10, N = 1010) a heterogeneous spectrum: approximately one-third of adults might have had prediabetes, almost half displayed some level of IR as reflected by HOMA-IR > 2.6, and serum calcium was positively correlated with HOMA-IR. Vitamin D deficiency was associated with a higher rate of metabolic syndrome (n = 1). Normocalcemic and mildly symptomatic hyperparathyroidism (n = 6, N = 193) was associated with a higher fasting glucose and some improvement after parathyroidectomy. This multilayer pancreas/parathyroid analysis highlighted a complex panel of connections from pathogenic factors, including biochemical, molecular, genetic, and metabolic factors, to a clinical multidisciplinary panel.
Assuntos
Hipercalcemia , Hiperparatireoidismo Primário , Resistência à Insulina , Pancreatite , Humanos , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/cirurgia , Hiperparatireoidismo Primário/complicações , Resistência à Insulina/genética , Hipercalcemia/genética , Hipercalcemia/etiologia , Pancreatite/genética , Pancreatite/etiologia , Feminino , Masculino , Proteínas Proto-Oncogênicas/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/cirurgia , Adulto , Paratireoidectomia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/patologia , Pâncreas/patologia , Pâncreas/cirurgia , Pâncreas/metabolismoRESUMO
Our objective was to overview the novel aspects in the field of adrenal gland neoplasms, namely, the management of bone status with respect to primary aldosteronism (PA). In the current narrative review, a PubMed study was conducted from inception until June 2023. The inclusion criteria were: human (clinically relevant) studies of any study design (at least 10 patients per study); English papers; and the following combination of key words within the title and/or abstract: "aldosterone" AND "bone", "skeleton", "osteoporosis", "fracture", "calcium", "parathyroid", "DXA", "osteocalcin", "P1NP", "alkaline phosphatase", "bone marker", "trabecular bone score", or "FRAX". The exclusion criteria were in vitro or animal studies, reviews, and case reports/series. We screened 1027 articles and finally included 23 studies (13 of case-control type, 3 cross-sectional, 5 prospective, 1 observational cohort, and 1 retrospective study). The assessments provided in these studies were as follows: nine studies addressed Dual-Energy X-ray Absorptiometry (DXA), another study pointed out a bone microarchitecture evaluation underlying trabecular bone score (TBS), and seven studies investigated the bone turnover markers (BTMs) profile. Moreover, 14 studies followed the subjects after adrenalectomy versus medical treatment, and 21 studies addressed secondary hyperparathyroidism in PA patients. According to our study on published data during a period of almost 40 years (n = 23, N = 3965 subjects aged between 38 and 64, with a mean age 56.75, and a female-to-male ratio of 1.05), a higher PTH in PA versus controls (healthy persons or subjects with essential hypertension) is expected, secondary hyperparathyroidism being associated in almost half of the adults diagnosed with PA. Additionally, mineral metabolism anomalies in PA may include lower serum calcium and higher urinary calcium output, all these three parameters being reversible under specific therapy for PA, regardless medical or surgical. The PA subgroup with high PTH seems at higher cardiovascular risk, while unilateral rather than bilateral disease was prone to this PTH anomaly. Moreover, bone mineral density (BMD) according to central DXA might show a higher fracture risk only in certain adults, TBS being a promising alternative (with a still unknown perspective of diabetes' influence on DXA-TBS results in PA). However, an overall increased fracture prevalence in PA is described in most studies, especially with respect to the vertebral site, the fracture risk that seems correctable upon aldosterone excess remission. These data recommend PA as a cause of secondary osteoporosis, a treatable one via PA intervention. There is still an area of debate the way to address BMTs profile in PA, the case's selection toward specific bone evaluation in every day practice, and further on, the understanding of the potential genetic influence at the level of bone and mineral complications in PA patients.
Assuntos
Neoplasias das Glândulas Suprarrenais , Hiperaldosteronismo , Hiperparatireoidismo Secundário , Osteoporose , Fraturas por Osteoporose , Adulto , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Fraturas por Osteoporose/etiologia , Estudos Retrospectivos , Cálcio , Estudos Transversais , Estudos Prospectivos , Vértebras Lombares , Densidade Óssea , Osso Esponjoso , Hiperaldosteronismo/complicações , Aldosterona , Neoplasias das Glândulas Suprarrenais/complicaçõesRESUMO
Diagnosis of primary hyperparathyroidism (PHP) is based on blood assessments in terms of synchronous high calcium and PTH (parathormone), but further management, particularly parathyroid surgery that provides the disease cure in 95-99% of cases, requires an adequate localisation of the parathyroid tumour/tumours as the originating source, with ultrasound and 99m-Technetium (99m-Tc) sestamibi scintigraphy being the most widely used. We aimed to introduce an adult female case diagnosed with PHP displaying unexpected intra-operatory findings (ectopic thyroid tissue) in relation to concordant pre-operatory imaging modalities (ultrasound + dual-phase 99m-Tc pertechnetate and sestamibi scintigraphy + computed tomography) that indicated bilateral inferior parathyroid tumours. A sudden drop in PTH following the removal of the first tumour was the clue for performing an extemporaneous exam for the second mass that turned out to be non-malignant ectopic thyroid tissue. We overviewed some major aspects starting from this case in point: the potential pitfalls of pre-operatory imaging in PHP; the concordance/discordance of pre-parathyroidectomy localisation modalities; the need of using an additional intra-operatory procedure; and the clues of providing a distinction between pathological parathyroids and thyroid tissue. This was a case of adult PHP, whereas triple localisation methods were used before parathyroidectomy, showing concordant results; however, the second parathyroid adenoma was a false positive image and an ectopic thyroid tissue was confirmed. The pre-operatory index of suspicion was non-existent in this patient. Hybrid imaging modalities are most probably required if both thyroid and parathyroid anomalies are suspected, but, essentially, awareness of the potential pitfalls is mandatory from the endocrine and surgical perspectives. Current gaps in imaging knowledge to guide us in this area are expected to be solved by the significant progress in functional imaging modalities. However, the act of surgery, including the decision of a PTH assay or extemporaneous exam (as seen in our case), represents the key to a successful removal procedure. Moreover, many parathyroid surgeons may currently perform 4-gland exploration routinely, precisely to avoid the shortcomings of preoperative localisation.
Assuntos
Hiperparatireoidismo , Neoplasias das Paratireoides , Doenças da Glândula Tireoide , Disgenesia da Tireoide , Adulto , Humanos , Feminino , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/cirurgia , Paratireoidectomia/métodos , Pertecnetato Tc 99m de Sódio , Tecnécio , Hiperparatireoidismo/diagnóstico por imagem , Hiperparatireoidismo/cirurgia , Sensibilidade e Especificidade , Compostos Radiofarmacêuticos , Cintilografia , Tecnécio Tc 99m Sestamibi , Compostos de Organotecnécio , Disgenesia da Tireoide/cirurgiaRESUMO
Petrified ear (PE), an exceptional entity, stands for the calcification ± ossification of auricular cartilage (CAC/OAC); its pathogenic traits are still an open matter. Endocrine panel represents one of the most important; yet, no standard protocol of assessments is available. Our objective was to highlight most recent PE data and associated endocrine (versus non-endocrine) ailments in terms of presentation, imagery tools, hormonal assessments, biopsy, outcome, pathogenic features. This was a comprehensive review via PubMed search (January 2000-March 2024). A total of 75 PE subjects included: 46 case reports/series (N = 49) and two imagery-based retrospective studies (N = 26) with CAC/OAC prevalence of 7-23% (N = 251) amid routine head/temporal bone CT scans. Endocrine PE (EPE): N = 23, male/female ratio = 10.5; average age = 56.78, ranges: 22-79; non-EPE cohort: N = 26; male/female ratio = 1.88, mean age = 49.44; ranges: 18-75 (+a single pediatric case).The longest post-diagnosis follow-up was of 6-7 years. The diagnosis of PE and endocrine anomalies was synchronous or not (time gap of 10-20 years). A novel case in point (calcified EPE amid autoimmune poly-endocrine syndrome type 2 with a 10-year post-diagnosis documented follow-up) was introduced. We re-analyzed EPE and re-classified another five subjects as such. Hence, the final EPE cohort (N = 50) showed: adrenal insufficiency was the most frequent endocrine condition (36%) followed by hypopituitarism (22%) and hypothyroidism (18%); 39% of the patients with adrenal failure had Addison's disease; primary type represented 72% of all cases with hypothyroidism; an endocrine autoimmune (any type) component was diagnosed in 18%. We propose the term of "endocrine petrified ear" and a workflow algorithm to assess the potential hormonal/metabolic background in PE.
RESUMO
Brown tumors, an exceptional bone complication of severe primary (PHP) or renal (secondary) hyperparathyroidism (RHP), are caused by long-standing, elevated parathormone (PTH)-induced osteoclast activation causing multinucleated giant cell conglomerates with hemosiderin deposits in addition to the local production of cytokines and growth factors. We aim to present an adult case series including two females displaying this complication as part of a multidisciplinary complex panel in high PTH-related ailments. The approach was different since they had distinct medical backgrounds and posed a wide area of challenges amid real-life settings, namely, a 38-year-old lady with PHP and long-term uncontrolled hypercalcemia (with a history of pregnancy-associated PHP, the removal of a cystic jaw tumor, as well as a family and personal positive diagnosis of polycystic kidney disease, probably a PHP-jaw tumor syndrome), as well as, a 26-year-old woman with congenital single kidney and chronic renal disease-associated RHP who was poorly controlled under dialysis and developed severe anemia and episodes of metabolic acidosis (including one presentation that required emergency hemodialysis and was complicated with convulsive seizures, followed by resuscitated respiratory arrest). Both subjects displayed a severe picture of PHP/RHP with PTH levels of >1000 pg/mL and >2000 pg/mL and elevated serum bone turnover markers. Additionally, they had multiple brown tumors at the level of the ribs and pelvis (asymptomatically) and the spine, skull, and pelvis (complicated with a spontaneous cervical fracture). As an endocrine approach, the control of the underlying parathyroid disease was provided via surgery in PHP (for the postparathyroidectomy hungry bone syndrome) via medical intervention (with vitamin D analogs) in RHP. Additionally, in this case, since the diagnosis was not clear, a multidisciplinary decision to perform a biopsy was taken (which proved inconclusive), and the resection of the skull tumor to confirm the histological traits. This series highlights the importance of addressing the entire multidisciplinary panel of co-morbidities for a better outcome in patients with PHP/RHP-related brown tumors. However, in the instance of real-life medicine, poor compliance and reduced adherence to recommendations might impair the overall health status. Thus, sometimes, a direct approach at the level of cystic lesion is taken into consideration; this stands for a narrow frame of decision, and it is a matter of personalized decision. As seen here, brown tumors represent the hidden face of PHP/RHP, primarily the complex and severe forms, and awareness is essential even in the modern era.
RESUMO
We aimed to analyze the management of the ectopic mediastinal thyroid (EMT) with respect to EMT-related cancer and non-malignant findings related to the pathological report, clinical presentation, imaging traits, endocrine profile, connective tissue to the cervical (eutopic) thyroid gland, biopsy or fine needle aspiration (FNA) results, surgical techniques and post-operatory outcome. This was a comprehensive review based on revising any type of freely PubMed-accessible English, full-length original papers including the keywords "ectopic thyroid" and "mediastinum" from inception until March 2024. We included 89 original articles that specified EMTs data. We classified them into four main groups: (I) studies/case series (n = 10; N = 36 EMT patients); (II) malignant EMTs (N = 22 subjects; except for one newborn with immature teratoma in the EMT, only adults were reported; mean age of 62.94 years; ranges: 34 to 90 years; female to male ratio of 0.9). Histological analysis in adults showed the following: papillary (N = 11/21); follicular variant of the papillary type (N = 2/21); Hürthle cell thyroid follicular malignancy (N = 1/21); poorly differentiated (N = 1/21); anaplastic (N = 2/21); medullary (N = 1/21); lymphoma (N = 2/21); and MALT (mucosa-associated lymphoid tissue) (N = 1/21); (III) benign EMTs with no thyroid anomalies (N = 37 subjects; mean age of 56.32 years; ranges: 30 to 80 years; female to male ratio of 1.8); (IV) benign EMTs with thyroid anomalies (N = 23; female to male ratio of 5.6; average age of 52.1 years). This panel involved clinical/subclinical hypothyroidism (iatrogenic, congenital, thyroiditis-induced, and transitory type upon EMT removal); thyrotoxicosis (including autonomous activity in EMTs that suppressed eutopic gland); autoimmune thyroiditis/Graves's disease; nodules/multinodular goiter and cancer in eutopic thyroid or prior thyroidectomy (before EMT detection). We propose a 10-item algorithm that might help navigate through the EMT domain. To conclude, across this focused-sample analysis (to our knowledge, the largest of its kind) of EMTs, the EMT clinical index of suspicion remains low; a higher rate of cancer is reported than prior data (18.8%), incident imagery-based detection was found in 10-14% of the EMTs; surgery offered an overall good outcome. A wide range of imagery, biopsy/FNA and surgical procedures is part of an otherwise complex personalized management.
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Bone fragility is a complication of type 2 diabetes mellitus (T2DM) that has been identified in recent decades. Trabecular bone score (TBS) appears to be more accurate than bone mineral density (BMD) in diabetic bone disease, particularly in menopausal women with T2DM, to independently capture the fracture risk. Our purpose was to provide the most recent overview on TBS-associated clinical data in T2DM. The core of this narrative review is based on original studies (PubMed-indexed journals, full-length, English articles). The sample-based analysis (n = 11, N = 4653) confirmed the use of TBS in T2DM particularly in females (females/males ratio of 1.9), with ages varying between 35 and 91 (mean 65.34) years. With concern to the study design, apart from the transversal studies, two others were prospective, while another two were case-control. These early-post-pandemic data included studies of various sample sizes, such as: males and females (N of 245, 361, 511, and 2294), only women (N of 80, 96, 104, 243, 493, and 887), and only men (N = 169). Overall, this 21-month study on published data confirmed the prior profile of BMD-TBS in T2DM, while the issue of whether checking the fracture risk is mandatory in adults with uncontrolled T2DM remains to be proven or whether, on the other hand, a reduced TBS might function as a surrogate marker of complicated/uncontrolled T2DM. The interventional approach with bisphosphonates for treating T2DM-associated osteoporosis remains a standard one (n = 2). One control study on 4 mg zoledronic acid showed after 1 year a statistically significant increase of lumbar BMD in both diabetic and non-diabetic groups (+3.6%, p = 0.01 and +6.2%, p = 0.01, respectively). Further studies will pinpoint additive benefits on glucose status of anti-osteoporotic drugs or will confirm if certain glucose-lowering regimes are supplementarily beneficial for fracture risk reduction. The novelty of this literature research: these insights showed once again that the patients with T2DM often have a lower TBS than those without diabetes or with normal glucose levels. Therefore, the decline in TBS may reflect an early stage of bone health impairment in T2DM. The novelty of the TBS as a handy, non-invasive method that proved to be an index of bone microarchitecture confirms its practicality as an easily applicable tool for assessing bone fragility in T2DM.
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Our aim is to update the topic of adrenal tumours (ATs) in congenital adrenal hyperplasia (CAH) based on a multidisciplinary, clinical perspective via an endocrine approach. This narrative review is based on a PubMed search of full-length, English articles between January 2014 and July 2023. We included 52 original papers: 9 studies, 8 case series, and 35 single case reports. Firstly, we introduce a case-based analysis of 59 CAH-ATs cases with four types of enzymatic defects (CYP21A2, CYP17A1, CYP17B1, and HSD3B2). Secondarily, we analysed prevalence studies; their sample size varied from 53 to 26,000 individuals. AT prevalence among CAH was of 13.3-20%. CAH prevalence among individuals with previous imaging diagnosis of AT was of 0.3-3.6%. Overall, this 10-year, sample-based analysis represents one of the most complex studies in the area of CAH-ATs so far. These masses should be taken into consideration. They may reach impressive sizes of up to 30-40 cm, with compressive effects. Adrenalectomy was chosen based on an individual multidisciplinary decision. Many tumours are detected in subjects with a poor disease control, or they represent the first step toward CAH identification. We noted a left lateralization with a less clear pathogenic explanation. The most frequent tumour remains myelolipoma. The risk of adrenocortical carcinoma should not be overlooked. Noting the increasing prevalence of adrenal incidentalomas, CAH testing might be indicated to identify non-classical forms of CAH.