MANAGEMENT OF ENDOCRINE DISEASE: Unmet therapeutic, educational and scientific needs in parathyroid disorders

Abstract

PARAT, a new European Society of Endocrinology program, aims to identify unmet scientific and educational needs of parathyroid disorders, such as primary hyperparathyroidism (PHPT), including parathyroid cancer (PC), and hypoparathyroidism (HypoPT). The discussions and consensus statements from the first PARAT workshop (September 2018) are reviewed. PHPT has a high prevalence in Western communities, PHPT has a high prevalence in Western communities, yet evidence is sparse concerning the natural history and whether morbidity and long-term outcomes are related to hypercalcemia or plasma PTH concentrations, or both. Cardiovascular mortality and prevalence of low energy fractures are increased, whereas Quality of Life is decreased, although their reversibility by treatment of PHPT has not been convincingly demonstrated. PC is a rare cause of PHPT, with an increasing incidence, and international collaborative studies are required to advance knowledge of the genetic mechanisms, biomarkers for disease activity, and optimal treatments. For example, ~20% of PCs demonstrate high mutational burden, and identifying targetable DNA variations, gene amplifications and gene fusions may facilitate personalized care, such as different forms of immunotherapy or targeted therapy. HypoPT, a designated orphan disease, is associated with a high risk of symptoms and complications. Most cases are secondary to neck surgery. However, there is a need to better understand the relation between disease biomarkers and intellectual function, and to establish the role of PTH in target tissues, as these may facilitate the appropriate use of PTH substitution therapy. Management of parathyroid disorders is challenging, and PARAT has highlighted the need for international transdisciplinary scientific and educational studies in advancing in this field.

Figure 1

Ultrasound image of a parathyroid carcinoma. The tumor (arrows), located at the upper pole of the thyroid, shows a heterogeneous pattern, irregular shape and halo sign (longitudinal view) (from Cetani et al. JEI 2016, with permission (18)).

Figure 2

Histopathology: Parathyroid carcinoma in the context of CDC73-related disorder. Concerns index patient III.2 of family G described by van der Tuin et al. (Supplementary Fig. 1 and Supplementary Table 1 in the reference (38)). This male patient was diagnosed with PC at the age 45 years after he presented with primary hyperparathyroidism and a right-sided mass in the neck of 6 cm with lymph node metastases. The patient eventually died of this disease. Germ line CDC73 (HRPT2) analysis showed a large deletion of the q-arm of chromosome 1 including the complete CDC73 gene. In the upper part of the figure, a hematoxylin and eosin stained histological slide is presented. The tumour showed pleiomorphic parathyroid hormone positive staining cells with anisokaryosis and prominent nucleoli. Broad fibrous bands were between tumour cell islands. Occasionally mitoses were observed. The Ki-67 index was focally around 5%. Lymph angio-invasiveness outside the tumour mass was seen. Parafibromin immunohistochemistry showed vague positive and focal complete lack of nuclear staining of tumour cell in comparison with internal reference cells. There was enhanced cytoplasmic staining of tumour cells. In the lower part of the figure somatic CDC73 (HRPT2) Sanger DNA-sequencing results are depicted showing a forward reference sequence above the tumour sequence. This region was not well covered in a targeted CDC73 containing gene panel for next-generation sequencing that was also analysed. In the tumour as a second hit on the wild type allele a pathogenic CDC73 exon 1: c.91_92delinsGGAA, p.(Ser31Glyfs*7) gene variant was identified.

Figure 3

Overall calcium homeostasis in chronic hypoparathyroidism. In chronic hypoparathyroidism in adults, overall calcium metabolism is reflected by the lack of PTH. Bone turnover is markedly decreased as is the net release of calcium from the stores in bone. Levels of active vitamin D (1.25-(OH)₂–Vit D) are low due to lack of the PTH driven 1-α-hydroxylase followed by decreased intestinal absorption of calcium. The renal tubular reabsorption of calcium is decreased. Moreover, phosphate levels are high – not illustrated in the figure.

Figure 4

Overall calcium homeostasis in primary hyperparathyroidism. Due to a set-point error in PHPT, circulating PTH levels are inappropriately increased leading to a new steady state with increased PTH and calcium levels. Bone turnover, the renal tubular reabsorption of calcium, the activation of vitamin D followed by calcium absorption from the gut are all increased leading to the new steady state, which in principle is able to be regulated – just at a higher level.