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Frontiers in Bioscience (Landmark... Aug 2023Parathyroid hormone (PTH) is an endocrine peptide found exclusively in the parathyroid glands, whereas parathyroid hormone-related protein (PTHrP) is expressed in a wide... (Review)
Review
Parathyroid hormone (PTH) is an endocrine peptide found exclusively in the parathyroid glands, whereas parathyroid hormone-related protein (PTHrP) is expressed in a wide range of tissues and organs and exerts endocrine, paracrine, and autocrine actions. PTH and PTHrP have a similar homology, sharing the initial 13 amino acid residues at the N-terminus and binding to the same type 1 PTH receptor (PTH1R), which regulates calcium homeostasis. An abnormal increase in PTH production can occur in primary and secondary hyperparathyroidism, whereas PTHrP can be produced in large quantities by malignant cancer cells from solid organs. In addition to increased bone resorption and hypercalcemia, recent evidence suggests that excess PTH and PTHrP can result in protein-energy wasting, malnutrition, and cachexia. Through binding to PTH1R and activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A in white adipose tissue, PTH and PTHrP can stimulate the expression of thermogenic genes causing adipose tissue browning. This change results in an increase in resting energy expenditure, loss of muscle and fat mass, and weight loss. These findings provide a mechanistic link for the long-established relationship between hyperparathyroidism and myopathy, as well as cancer and cachexia. The purpose of this review is to provide a summary of the emerging evidence from both experimental and clinical studies on the role of PTH and PTHrP in protein-energy malnutrition.
Topics: Humans; Adipose Tissue; Cachexia; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Protein-Energy Malnutrition
PubMed: 37664938
DOI: 10.31083/j.fbl2808167 -
Casopis Lekaru Ceskych 2023Hypoparathyroidism is a rare endocrine disease caused by an absence or insufficient production of parathormone. Parathormone deficiency leads to lower serum calcium...
Hypoparathyroidism is a rare endocrine disease caused by an absence or insufficient production of parathormone. Parathormone deficiency leads to lower serum calcium concentration that is responsible for patients' neuromuscular symptoms. Conventional treatment consists of calcium and active vitamin D metabolites administration but doesn't constitute an adequate substitution of missing parathormone. Although the treatment substantially alleviates patients' troubles, chronic complications may develop because of hyperphosphatemia and conventional medication. Solution to this resides in recombinant parathormone administration, however the only one drug available is being now recalled from the market. The mainstay of hypoparathyroidism prevention is the judicious indication of total thyroidectomy representing the main cause of the disease.
Topics: Humans; Calcium; Hypoparathyroidism; Parathyroid Hormone; Rare Diseases
PubMed: 37734939
DOI: No ID Found -
Nature Feb 2024Many peptide hormones form an α-helix on binding their receptors, and sensitive methods for their detection could contribute to better clinical management of disease....
Many peptide hormones form an α-helix on binding their receptors, and sensitive methods for their detection could contribute to better clinical management of disease. De novo protein design can now generate binders with high affinity and specificity to structured proteins. However, the design of interactions between proteins and short peptides with helical propensity is an unmet challenge. Here we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that by extending RFdiffusion to enable binder design to flexible targets, and to refining input structure models by successive noising and denoising (partial diffusion), picomolar-affinity binders can be generated to helical peptide targets by either refining designs generated with other methods, or completely de novo starting from random noise distributions without any subsequent experimental optimization. The RFdiffusion designs enable the enrichment and subsequent detection of parathyroid hormone and glucagon by mass spectrometry, and the construction of bioluminescence-based protein biosensors. The ability to design binders to conformationally variable targets, and to optimize by partial diffusion both natural and designed proteins, should be broadly useful.
Topics: Biosensing Techniques; Computer-Aided Design; Deep Learning; Diffusion; Glucagon; Luminescent Measurements; Mass Spectrometry; Parathyroid Hormone; Peptides; Protein Structure, Secondary; Proteins; Substrate Specificity; Models, Molecular
PubMed: 38109936
DOI: 10.1038/s41586-023-06953-1 -
Current Opinion in Endocrinology,... Aug 2024Since the release of the 2022 Second International Workshop Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines, updates and advances are... (Review)
Review
PURPOSE OF REVIEW
Since the release of the 2022 Second International Workshop Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines, updates and advances are now available in the cause, complications, and treatment of adult chronic hypoparathyroidism (hypoPTH). This review aims to highlight these new findings and implications to patient care.
RECENT FINDINGS
Postsurgical hypoparathyroidism remains the most common cause, immune-related hypoparathyroidism from checkpoint inhibitors is an emerging autoimmune cause. In a large retrospective cohort study of thyroidectomies, incident fracture was lower, particularly in the vertebra, in the hypoPTH cohort, compared with postthyroidectomy control group. Hypercalciuria increases risk for renal calculi in hypoPTH independent of disease duration and treatment dose. Quality of life is impaired in hypoPTH patients on conventional therapy, improvement was noted post-PTH replacement. TranCon PTH phase 3 RCT reported eucalcemia with reduced renal calcium excretion, normalization of bone turn-over markers, stable BMD and improved quality of life.
SUMMARY
HypoPTH is a chronic disease associated with significant morbidity and poor Quality of Life. Awareness of treatment targets and follow-up investigations can alleviate patient anxiety regarding over-treatment and under-treatment. Progress in long-acting PTH replacement strategies might provide accessible, feasible alternatives to conventional therapy in brittle hypoPTH patients.
Topics: Hypoparathyroidism; Humans; Quality of Life; Thyroidectomy; Parathyroid Hormone; Postoperative Complications; Hormone Replacement Therapy; Adult; Chronic Disease
PubMed: 38767063
DOI: 10.1097/MED.0000000000000868 -
Nephrology, Dialysis, Transplantation :... Mar 2024Calcimimetics are widely used in hemodialysis patients and influence serum calcium levels. Although the Kidney Disease: Improving Global Outcomes guidelines argued that...
BACKGROUND
Calcimimetics are widely used in hemodialysis patients and influence serum calcium levels. Although the Kidney Disease: Improving Global Outcomes guidelines argued that low calcium levels induced by calcimimetics may be harmless, large observational studies investigating the association between hypocalcemia and mortality are scarce. We investigated the association between serum calcium levels and cardiovascular mortality in calcimimetics users using the nationwide Japanese registry for dialysis patients.
METHODS
In this 9-year prospective cohort study, the baseline data were collected at the end of 2009. We enrolled patients on maintenance hemodialysis or hemodiafiltration. We employed three models (baseline, time-dependent and time-averaged) to conduct Cox proportional hazard regression analyses.
RESULTS
Cinacalcet was prescribed to 12.7% (N = 22 853) at baseline. The median observation period was 98 (interquartile range 40-108) months and 108 (interquartile range 59-108) months in the whole cohort (N = 180 136) and in cinacalcet users, respectively. Three-quarters of survivors at the end of 2019 had continued calcimimetic therapy for 10 years, corresponding to a mean annual dropout rate of 2.9%. Hypocalcemia was not associated with cardiovascular mortality in the baseline or time-averaged model. In the time-dependent model, however, the lowest calcium decile (corrected calcium <8.4 mg/dL) was significantly associated with higher cardiovascular mortality than the reference (corrected calcium 8.7-8.9 mg/dL) in both cinacalcet users and all patients [hazard ratio (95% confidence interval) 1.32 (1.00, 1.75) and 1.15 (1.05, 1.26), respectively]. Hypocalcemia was especially associated with sudden death and death due to hemorrhagic stroke, heart failure and ischemic heart disease. Higher rate of fatal and non-fatal cardiovascular events was observed in hypocalcemic patients regardless of cinacalcet usage.
CONCLUSIONS
Our findings suggest that transient hypocalcemia was associated with an increased risk of cardiovascular death independent of cinacalcet usage. We should pay attention to hypocalcemia transiently induced by cinacalcet.
Topics: Humans; Cinacalcet; Hypocalcemia; Calcium; Prospective Studies; Renal Dialysis; Parathyroid Hormone; Hyperparathyroidism, Secondary; Calcimimetic Agents; Heart Failure
PubMed: 37777840
DOI: 10.1093/ndt/gfad213 -
Otolaryngologic Clinics of North America Feb 2024Primary hyperparathyroidism is the most common cause of hypercalcemia, accounting for about 90% of all cases. This disorder is characterized by overactive parathyroid... (Review)
Review
Primary hyperparathyroidism is the most common cause of hypercalcemia, accounting for about 90% of all cases. This disorder is characterized by overactive parathyroid glands, leading to increased parathyroid hormone and excess serum calcium.
Topics: Humans; Calcium; Hyperparathyroidism; Parathyroid Glands; Parathyroid Hormone; Hypercalcemia
PubMed: 37634986
DOI: 10.1016/j.otc.2023.07.012 -
International Journal of Oral Science Aug 2023Orthodontically induced tooth root resorption (OIRR) is a serious complication during orthodontic treatment. Stimulating cementum repair is the fundamental approach for...
Orthodontically induced tooth root resorption (OIRR) is a serious complication during orthodontic treatment. Stimulating cementum repair is the fundamental approach for the treatment of OIRR. Parathyroid hormone (PTH) might be a potential therapeutic agent for OIRR, but its effects still lack direct evidence, and the underlying mechanisms remain unclear. This study aims to explore the potential involvement of long noncoding RNAs (lncRNAs) in mediating the anabolic effects of intermittent PTH and contributing to cementum repair, as identifying lncRNA-disease associations can provide valuable insights for disease diagnosis and treatment. Here, we showed that intermittent PTH regulates cell proliferation and mineralization in immortalized murine cementoblast OCCM-30 via the regulation of the Wnt pathway. In vivo, daily administration of PTH is sufficient to accelerate root regeneration by locally inhibiting Wnt/β-catenin signaling. Through RNA microarray analysis, lncRNA LITTIP (LGR6 intergenic transcript under intermittent PTH) is identified as a key regulator of cementogenesis under intermittent PTH. Chromatin isolation by RNA purification (ChIRP) and RNA immunoprecipitation (RIP) assays revealed that LITTIP binds to mRNA of leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) and heterogeneous nuclear ribonucleoprotein K (HnRNPK) protein. Further co-transfection experiments confirmed that LITTIP plays a structural role in the formation of the LITTIP/Lgr6/HnRNPK complex. Moreover, LITTIP is able to promote the expression of LGR6 via the RNA-binding protein HnRNPK. Collectively, our results indicate that the intermittent PTH administration accelerates root regeneration via inhibiting Wnt pathway. The lncRNA LITTIP is identified to negatively regulate cementogenesis, which activates Wnt/β-catenin signaling via high expression of LGR6 promoted by HnRNPK.
Topics: Mice; Animals; Cementogenesis; Wnt Signaling Pathway; beta Catenin; Heterogeneous-Nuclear Ribonucleoprotein K; RNA, Long Noncoding; Parathyroid Hormone; Receptors, G-Protein-Coupled
PubMed: 37558690
DOI: 10.1038/s41368-023-00237-0 -
Khirurgiia 2024To study the features of clinical course, diagnosis and treatment of true non-functioning parathyroid cysts.
OBJECTIVE
To study the features of clinical course, diagnosis and treatment of true non-functioning parathyroid cysts.
MATERIAL AND METHODS
We retrospectively analyzed 18 patients with non-functioning true parathyroid cysts. Inclusion criteria: US-confirmed anechoic lesion of the neck without tissue component, cytological data on cystic lesion, high cystic parathyroid hormone and no laboratory signs of hyperparathyroidism.
RESULTS
Non-functioning parathyroid cysts were asymptomatic and diagnosed accidentally after ultrasound of the neck. All patients were women aged 35-77 years. Four patients had cysts near the upper parathyroid glands, 14 patients - near the lower parathyroid glands. Of these, 2 ones had cysts below the level of the clavicle. Cyst volume was 4.3-110.3 cm (24.1±26.2 cm). High cystic parathyroid hormone (2012.5±946.7 pg/ml) was observed in all patients. Simple aspiration was performed in 5 patients, aspiration with sclerotherapy - in 10 patients, cystectomy - in 3 patients. Recurrence was diagnosed in 1 patient after aspiration and 2 patients after sclerotherapy.
CONCLUSION
No pathognomonic clinical and ultrasonic symptoms, as well as specific cytological data lead to misdiagnosis. Analysis of PTH in non-functioning parathyroid cysts is essential for diagnosis. Minimally invasive treatment is preferable for true parathyroid cysts. However, these approaches are not radical.
Topics: Humans; Female; Male; Retrospective Studies; Parathyroid Diseases; Hyperparathyroidism; Parathyroid Hormone; Cysts
PubMed: 38344962
DOI: 10.17116/hirurgia202402168 -
Annales D'endocrinologie Aug 2023Treatment of chronic hypoparathyroidism remains a therapeutic challenge. In three quarters of cases, this endocrine disorder arises as a consequence of neck surgery, but... (Review)
Review
Treatment of chronic hypoparathyroidism remains a therapeutic challenge. In three quarters of cases, this endocrine disorder arises as a consequence of neck surgery, but it can also present in other disease settings, for example, in rare genetic disorders. Conventional standard of care treatment is based on oral administration of calcium and vitamin D. However, a significant proportion of patients remain uncontrolled biochemically under this treatment, with persistent clinical symptoms that affect quality of life. Administration of parathyroid hormone (PTH) in more recent times has encountered the problem of the short half-life of the hormone, which necessitates multiple daily injections or continuous subcutaneous administration controlled by a pump. Recently, progress in understanding the pathophysiology of hypoparathyroidism has opened the possibility of new therapeutic approaches using longer-acting forms of PTH, PTH receptor analogs or, more recently, calcilytic agents. These are the subjects of current clinical trials, with encouraging results. However, their possible future use will depend on their long-term impacts on bone metabolism and renal function, which remain to be determined.
Topics: Humans; Quality of Life; Hypoparathyroidism; Parathyroid Hormone; Calcium; Vitamin D
PubMed: 37080533
DOI: 10.1016/j.ando.2023.04.001 -
Annals of Saudi Medicine 2023Neonatal severe hyperparathyroidism (NSHPT) is a rare disease that can be lethal. Most patients require parathyroidectomy. (Review)
Review
BACKGROUND
Neonatal severe hyperparathyroidism (NSHPT) is a rare disease that can be lethal. Most patients require parathyroidectomy.
OBJECTIVE
Report experience in managing this severe disease.
DESIGN
Retrospective chart review of case series.
SETTING
Tertiary health care center.
PATIENTS AND METHODS
We reviewed data on patients managed for NSHPT from June 2001 to January 2023. Demographic, clinical, and follow-up data were collected, and descriptive data were generated.
MAIN OUTCOME MEASURES
Pre- and postoperative levels of parathyroid hormone (PTH) and serum calcium, and effect of autotransplantation.
SAMPLE SIZE
19.
RESULTS
The 13 males and 6 females had a a mean age of 46 days at referral. The mean preoperative parathyroid hormone (PTH) and serum calcium levels were 996 ng/L and 4.54 mmol/L, respectively. Twelve patients underwent ultrasonography preoperatively. Of these, six had prominent glands, while no glands were seen in the other six. A Sestamibi scan was done for 15 patients, of which nine showed negative results and six showed positive results, with three glands observed in the neck and three in the sublingual area. Nineteen patients underwent renal ultrasonography, with nine showing nephrocalcinosis. The mean age at surgery was 5.2 months. Total parathyroidectomy (four glands) was performed in 17 patients, and 15 underwent concurrent auto-transplantation. One patient had three glands removed, in addition to auto-transplantation. Another underwent single gland excision as a redo-surgery after previous surgery elsewhere. The mean postoperative follow-up duration was 6 years. The mean postoperative PTH and calcium levels were 25 ng/L and 1.64 mmol/L, respectively. Ultimately, all the patients were required to initiate calcium and vitamin D supplements, except for two patients who had undergone auto-transplantation. Molecular genetic screening of the calcium-sensing receptor gene reported likely pathogenic/pathogenic mutations in 16 of 19 patients (13 were homozygous, two were heterozygous, one was negative, and data was unavailable for the remaining three patients).
CONCLUSIONS
Surgical treatment of NSHPT is effective. Preoperative radiological localization studies did not impact the treatment plan. Auto-transplantation proved ineffective in maintaining independence from medical supplements.
LIMITATIONS
The retrospective nature of the study may imply inaccuracybut since the data are gathered from electronic medical records, we believe it is highly accurate. The small sample size limits generalizability.
Topics: Male; Infant, Newborn; Female; Humans; Infant; Parathyroid Glands; Calcium; Retrospective Studies; Hyperparathyroidism, Primary; Parathyroid Hormone
PubMed: 37916585
DOI: 10.5144/0256-4947.2023.01.11.1200