SEARCHNARRATIVE_REVIEWendocrinology, ophthalmology

narrative_review·endocrinology, ophthalmology, nephrology, neurology, surgery·PMC10364481

Etiology and Pathophysiology of Hypoparathyroidism: A Narrative Review

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 13 authors, 13 centres

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This narrative review summarizes the etiologies and pathophysiology of hypoparathyroidism, with approximately 75% of cases being postsurgical and 25% due to genetic, autoimmune, or other nonsurgical causes. Key complications include renal (nephrolithiasis up to 36%, nephrocalcinosis up to 38%), skeletal (increased bone mass with reduced remodeling), neurological (seizures in 40-60%, basal ganglia calcification in 60-90%), and ocular (cataracts in 46-58%) manifestations, significantly impacting quality of life. The review highlights the importance of intraoperative parathyroid preservation and standardized postoperative monitoring to reduce the burden of this chronic endocrinopathy.

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**Background:** Hypoparathyroidism is a rare disorder characterized by impaired or inadequate parathyroid hormone (PTH) secretion, leading to hypocalcemia and hyperphosphatemia. The estimated prevalence is ~23 to 37 cases per 100,000 person-years. Approximately 75% of cases are iatrogenic following neck surgery, while ~25% arise from genetic, autoimmune, metabolic, or infiltrative disorders. This narrative review systematically examines the etiologies and pathophysiology of hypoparathyroidism, with a focus on postsurgical causes and multisystem complications.

**Methods:** The review was prepared in consultation with a medical librarian, executing a comprehensive search in PubMed and Embase for articles published from 1980 to 2020 in English. Inclusion criteria required primary data focusing on etiology and pathophysiology of hypoparathyroidism. Exclusion criteria included articles not primarily on etiology/pathophysiology, those focused on genetic etiologies (covered elsewhere), conference abstracts, opinion pieces, commentaries, letters, and case reports. Two independent reviewers screened abstracts and full texts. Cited reference searching and expert recommendations supplemented the search. Results were presented in a PRISMA flow diagram. Meta-analysis and risk-of-bias assessment were not performed due to the noninterventional nature of the data.

**Key Results:** - **Postsurgical hypoparathyroidism:** Temporary hypoparathyroidism occurs in 14% to 43% of patients after bilateral thyroid surgery, while permanent rates range from 1% to 25%. A Swedish registry study found 12.5% of patients remained hypoparathyroid 1 year after surgery. NSQIP data showed 5.8% (428/7366) experienced severe hypocalcemia post-thyroidectomy. Risk factors include inadvertent parathyroidectomy (OR 1.90), Graves' disease (OR 1.75), central neck dissection (RR 2.35), reoperation (RR 1.81), and low surgeon volume (OR 2.94). Incidental parathyroidectomy occurs in 12.4% of cases (range 16.9% to 43.6% in one study) and increases risk of permanent hypoparathyroidism (6.7% vs 2.2%, RR 3.10). Autotransplantation correlates with higher rates of hypoparathyroidism (meta-analysis of 25 studies). Intraoperative PTH monitoring: therapy should be started if iPTH drops below 10 pg/mL or declines >70% from preoperative values at 4 hours post-surgery. Recovery occurs in 70-80% within 1 month, and 75% of those with protracted hypoparathyroidism recover within 12 months. - **Nonsurgical etiologies:** ~25% of cases are due to genetic disorders (e.g., DiGeorge syndrome, CASR mutations), autoimmune destruction (isolated or as part of APS-1/APECED), radiation, toxins (e.g., L-asparaginase, nivolumab), metabolic disorders (e.g., severe burns, magnesium abnormalities), maternal hypercalcemia, or idiopathic causes. - **Renal complications:** Nephrolithiasis occurs in up to 36% of patients, nephrocalcinosis in up to 38%, and chronic kidney disease (CKD) in 2.5% to 41%. CKD progression risk is higher in chronic hypoparathyroidism. - **Skeletal manifestations:** Increased bone mass in cortical and cancellous compartments. Histomorphometry shows reduced mineralizing surface (58% decrease), bone formation rate (80% decrease), and remodeling activation frequency (54% decrease) compared to controls. Resorption depth reduced, resorption period increased from 26 to 80 days. - **Neurologic/psychiatric manifestations:** Tetany, muscle stiffness, and seizures occur in 40-60% of patients. Seizures are generalized tonic-clonic in 80% of cases. Basal ganglia calcification (BGC) prevalence is 60-90%, increasing to 93% after >20 years of disease. Neuropsychological symptoms include anxiety (47%), depressive mood (40%), tension (55%), and extrapyramidal features (15%). - **Ocular manifestations:** Cataract prevalence is 46-58%, with average age of surgery at 35 years. Posterior capsular opacification (75%) and lens decentralization (25%) are unique post-surgical complications. - **Quality of life:** Chronic hypoparathyroidism negatively impacts QOL, with substantial burden on patients and caregivers.

**Clinical Implications:** The review underscores the need for proactive preservation of parathyroid glands during neck surgery, standardized postoperative monitoring (including iPTH and calcium levels), and long-term follow-up to detect complications. Early recognition and management of renal, skeletal, neurological, and ocular complications are critical. Emerging technologies like ICG angiography and near-infrared autofluorescence may improve intraoperative assessment of parathyroid viability. Future research should address unexplained idiopathic cases, optimal serum calcium targets, and the mechanisms underlying increased bone mass and QOL improvements with PTH therapy.

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narrative_review

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endocrinology

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ORIGINAL PAPER

PMC10364481

Etiology and Pathophysiology of Hypoparathyroidism: A Narrative Review

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

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ABSTRACT

The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of hypoparathyroidism. Enhanced attention by endocrine surgeons to new knowledge about parathyroid gland viability are reviewed along with the role of intraoperative parathyroid hormone (ioPTH) monitoring during and after neck surgery. Nonsurgical etiologies account for a significant proportion of cases of hypoparathyroidism (~25%), and among them, genetic etiologies are key. Given the pervasive nature of PTH deficiency across multiple organ systems, a detailed review of the skeletal, renal, neuromuscular, and ocular complications is provided. The burden of illness on affected patients and their caregivers contributes to reduced quality of life and social costs for this chronic endocrinopathy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

CITATION EXPORT

Janice L. Pasieka, Kelly Wentworth, Caitlin T. Yeo et al.. Etiology and Pathophysiology of Hypoparathyroidism: A Narrative Review. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. (2022). https://doi.org/10.1002/jbmr.4714

AUTHORS

13 · 13 CENTRES

Janice L. Pasieka, Kelly Wentworth, Caitlin T. Yeo, Serge Cremers, David Dempster, Seiji Fukumoto, Ravinder Goswami, Pascal Houillier, Michael A. Levine, Jesse D. Pasternak, Nancy D. Perrier, Antonio Sitges-Serra, Dolores M. Shoback

1Clinical Professor of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
2Assistant Adjunct Professor of Medicine, University of California, San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA
3Clinical Lecturer of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
4Associate Professor of Pathology and Cell Biology and Medicine, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY, USA
5Professor of Clinical Pathology and Cell Biology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY, USA
6Specially Appointed Professor, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
7Professor, Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India
8Département de Physiologie, Professor of Physiology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
9Professor Emeritus of Pediatrics and Medicine, University of Pennsylvania, Director, Center for Bone Health, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
10Endocrine Surgery Section Head, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada
11Professor of Surgery, University of Texas MD Anderson Cancer Center, Department of Surgical Oncology, Section of Surgical Endocrinology, Houston, TX, USA
12Emeritus Professor, Universitat Autònoma de Barcelona, Endocrine Surgery, Hospital del Mar, Barcelona, Spain
13Professor of Medicine, University of California, San Francisco, Endocrine Research Unit, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA