A clinical perspective of parathyroid hormone related hypercalcaemia

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Abstract

There are many causes of hypercalcaemia including hyperparathyroidism, drugs, granulomatous disorders and malignancy. Parathyroid hormone (PTH) related hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) and more rarely by familial hypocalciuric hypercalcaemia (FHH). Algorithms for diagnosis of PTH related hypercalcaemia require assessment of a 24-h urinary calcium and creatinine excretion to calculate calcium/creatinine clearance ratio and radiological investigations including ultrasound scan and ^99mTc-sestamibi-SPECT/CT. To illustrate investigations and management of parathyroid-related hypercalcaemia, we present a selection of distinct cases of PHPT due to eutopic and ectopic parathyroid adenomas, as well as a case with a syndromic form of PHPT (multiple endocrine neoplasia type 1), and a case with FHH type 1 due to a CASR inactivating mutation. Additional cases with normocalcaemic hyperparathyroidism and secondary hyperparathyroidism are included for completeness of differential diagnosis. The common eutopic parathyroid adenomas are easily treated with parathyroidectomy while the less common ectopic parathyroid adenomas require more complex investigations and operative procedures such as video-assisted thoracoscopic surgery. On the other hand, the much less common FHH does not require treatment. Assessment of kin with FHH is important to identify members with this inherited condition in order to prevent unnecessary interventions.

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Hyperparathyroidism

William Fraser (2009)

The Lancet, 374(9684), 145-158

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Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4)

Rajesh Thakker (2014)

Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence of specific tumors. Thus, MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors; MEN2 is characterized by the occurrence of medullary thyroid carcinoma (MTC) in association with phaeochromocytoma and parathyroid tumors; MEN3 is characterized by the occurrence of MTC and phaeochromocytoma in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibers and intestinal autonomic ganglion dysfunction, leading to megacolon; and MEN4, which is also referred to as MENX, is characterized by the occurrence of parathyroid and anterior pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs. This review will focus on the clinical and molecular details of the MEN1 and MEN4 syndromes. The gene causing MEN1 is located on chromosome 11q13, and encodes a 610 amino-acid protein, menin, which has functions in cell division, genome stability, and transcription regulation. Menin, which acts as scaffold protein, may increase or decrease gene expression by epigenetic regulation of gene expression via histone methylation. Thus, menin by forming a subunit of the mixed lineage leukemia (MLL) complexes that trimethylate histone H3 at lysine 4 (H3K4), facilitates activation of transcriptional activity in target genes such as cyclin-dependent kinase (CDK) inhibitors; and by interacting with the suppressor of variegation 3–9 homolog family protein (SUV39H1) to mediate H3K methylation, thereby silencing transcriptional activity of target genes. MEN1-associated tumors harbor germline and somatic mutations, consistent with Knudson’s two-hit hypothesis. Genetic diagnosis to identify individuals with germline MEN1 mutations has facilitated appropriate targeting of clinical, biochemical and radiological screening for this high risk group of patients for whom earlier implementation of treatments can then be considered. MEN4 is caused by heterozygous mutations of CDNK1B which encodes the 196 amino-acid CDK1 p27Kip1, which is activated by H3K4 methylation.

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Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop.

Pierre D'Amour, Rajesh Thakker, Karita Costa … (2014)

Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to provide an update on the use of diagnostic tests for this condition in clinical practice. This subgroup was constituted by the Steering Committee to address key questions related to the diagnosis of PHPT. Consensus was established at a closed meeting of the Expert Panel that followed. Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting. Consensus was achieved by a group meeting. Statements were prepared by all authors, with comments relating to accuracy from the diagnosis subgroup and by representatives from the participating professional societies. We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second- and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 4) serum 25-hydroxyvitamin D concentrations should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; 5) genetic testing has the potential to be useful in the differential diagnosis of familial hyperparathyroidism or hypercalcemia.

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Author and article information

Contributors

Thang S. Han:

ORCID: http://orcid.org/0000-0003-2570-0938

thang.han@rhul.ac.uk

Journal

Journal ID (nlm-ta): Rev Endocr Metab Disord

Journal ID (iso-abbrev): Rev Endocr Metab Disord

Title: Reviews in Endocrine & Metabolic Disorders

Publisher: Springer US (New York )

ISSN (Print): 1389-9155

ISSN (Electronic): 1573-2606

Publication date (Electronic): 3 December 2019

Publication date PMC-release: 3 December 2019

Publication date (Print): 2020

Volume: 21

Issue: 1

Pages: 77-88

Affiliations

[1 ]Stanhope Surgery, Stanhope Road, Waltham Cross, EN8 7DJ UK

[2 ]GRID grid.5337.2, ISNI 0000 0004 1936 7603, School of Physiology, Pharmacology and Neuroscience, , University of Bristol, ; Bristol, UK

[3 ]GRID grid.4464.2, ISNI 0000 0001 2161 2573, Institute of Cardiovascular Research, Royal Holloway, , University of London, ; Egham, UK

[4 ]GRID grid.451052.7, ISNI 0000 0004 0581 2008, Department of Endocrinology, , Ashford and St Peter’s NHS Foundation Trust, ; Chertsey, UK

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Thang S. Han http://orcid.org/0000-0003-2570-0938

Article

Publisher ID: 9529

DOI: 10.1007/s11154-019-09529-5

PMC ID: 7113199

PubMed ID: 31797261

SO-VID: 0d3f2811-58ca-43af-a4da-6348b8a9f48b

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Funded by: Royal Holloway University of London

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: ectopic parathyroid adenoma,familial hypocalciuric hypercalcaemia,multiple endocrine neoplasm (men) syndromes,calcium/creatinine clearance ratio

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: ectopic parathyroid adenoma, familial hypocalciuric hypercalcaemia, multiple endocrine neoplasm (men) syndromes, calcium/creatinine clearance ratio

A clinical perspective of parathyroid hormone related hypercalcaemia

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 48

Hyperparathyroidism

Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4)

Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop.

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