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Current evidence for recommendation of surgery, medical treatment and vitamin D repletion in mild primary hyperparathyroidism

Jens Bollerslev, Claudio Marcocci, Manuel Sosa, Jörgen Nordenström, Roger Bouillon, and Leif Mosekilde

Management of patients with mild primary hyperparathyroidism (PHPT) has been widely discussed because most patients today do not have specific symptoms. While surgery is always an option, the recommendations for treatment have shifted, which mostly reflects changes in clinical practice. In this study, we aimed to evaluate evidence for the current recommendations concerning operation vs observation, repletion with vitamin D (VitD) and alternative medical management.

Surgery is followed by normalisation of calcium and parathyroid hormone (PTH) and a decrease in bone turnover followed by an increase in bone mass. It is not known what the consequences would be for the frequency of fractures. Randomised studies have indicated beneficial effects of operation on quality of life (QoL), but the effects have been minor and inconsistent. Operation seems not to be superior to observation for cardiovascular risk factors. Although PHPT patients in average have slightly decreased plasma 25OH VitD, severe symptomatic VitD deficiency seems not to be a characteristic of PHPT patients in Europe. However, if present, we recommend VitD substitution before final decision on surgical treatment. It is unknown whether routine VitD supplementation should be offered preoperatively to all patients with mild PHPT or as part of long-term medical treatment.

Targeted medical management could be an option for patients with contraindications to surgery. Antiresorptive therapy might be appropriate for patients with a low bone mass to prevent further bone loss. Calcimimetics could be tried to control serum calcium levels although there is no evidence of an effect on the hypercalcaemic symptoms or the QoL. Combined therapy with calcimimetics and alendronate could be considered for patients with hypercalcaemia and overt bone disease.

Free access

Evidence for protein and mRNA TSHr expression in fibroblasts from patients with thyroid-associated ophthalmopathy (TAO) after adipocytic differentiation

Patrizia Agretti, Giuseppina De Marco, Melissa De Servi, Claudio Marcocci, Paolo Vitti, Aldo Pinchera, and Massimo Tonacchera

Objective: Thyroid-associated ophthalmopathy (TAO) is a chronic autoimmune disorder characterized by an increased volume of adipose/connective tissue in the human orbit.

Design: The aim of this study was to investigate the thyrotropin receptor (TSHr) expression in orbital fibroblasts from TAO patients undergoing adipocytic differentiation.

Methods: Retro-ocular tissue and skin were obtained from five patients undergoing orbital decompression surgery for TAO and placed in culture. Proliferating fibroblasts were subjected to adipocytic differentiation for 10 days. Total RNA was isolated from fibroblasts and was reverse transcribed. TSHr mRNA levels were determined by real-time PCR. cAMP was determined by radioimmunoassay (RIA) after fibroblast incubation with the substances to test.

Results: Orbital differentiated fibroblasts became rounded and acquired lipid droplets. The amount of TSHr mRNA in these fibroblasts was higher than fibroblasts not subjected to adipocytic differentiation. Immunocytochemical analysis showed TSHr protein in differentiated orbital fibroblasts. Differentiated orbital fibroblasts stimulated with bovine (b) TSH showed a cAMP production greater than that in paired undifferentiated cultures. A specific thyroid-inhibiting antibody (TBAb) inhibited cAMP production after bTSH challenge, and a thyroid-stimulating antibody (TSAb) stimulated cAMP production in differentiated fibroblasts.

Conclusions: We suggest that orbital fibroblasts subjected to adipocytic differentiation increase TSHr expression that responds specifically to bTSH and TSAb stimulation, and to TBAb inhibition.

Free access

Diabetes insipidus is an unfavorable prognostic factor for response to glucocorticoids in patients with autoimmune hypophysitis

Isabella Lupi, Mirco Cosottini, Patrizio Caturegli, Luca Manetti, Claudio Urbani, Daniele Cappellani, Ilaria Scattina, Enio Martino, Claudio Marcocci, and Fausto Bogazzi

Introduction

Autoimmune hypophysitis (AH) has a variable clinical presentation and natural history; likewise, its response to glucocorticoid therapy is often unpredictable.

Objective

To identify clinical and radiological findings associated with response to glucocorticoids.

Design and methods

12 consecutive patients with AH, evaluated from 2008 to 2016. AH was the exclusion diagnosis after ruling out other pituitary masses and secondary causes of hypophysitis. Mean follow-up time was 30 ± 27 months (range 12–96 months).

Results

MRI identified two main patterns of presentation: global enlargement of the pituitary gland or panhypophysitis (n = 4, PH), and pituitary stalk abnormality only, or infundibulo-neuro-hypophysitis (n = 8, INH). Multiple tropin defects were more common in PH (100%) than those in INH (28% P = 0.014), whereas diabetes insipidus was more common in INH (100%) than that in PH (50%; P = 0.028). All 4 PH and 4 out of 8 INH were treated with glucocorticoids. Pituitary volume significantly reduced in all PH patients (P = 0.012), defective anterior pituitary function recovered only in the two patients without diabetes insipidus (50%) and panhypopituitarism persisted, along with diabetes insipidus, in the remaining 2 (50%). In all INH patients, either treated or untreated, pituitary stalk diameter reduced (P = 0.008) but diabetes insipidus persisted in all.

Conclusions

Glucocorticoid therapy may improve anterior pituitary function in a subset of patients but has no effect on restoring posterior pituitary function. Diabetes insipidus appears as a negative prognostic factor for response to glucocorticoids.

Free access

Disease activity and lifestyle influence comorbidities and cardiovascular events in patients with acromegaly

Chiara Sardella, Daniele Cappellani, Claudio Urbani, Luca Manetti, Giulia Marconcini, Luca Tomisti, Isabella Lupi, Giuseppe Rossi, Ilaria Scattina, Martina Lombardi, Vitantonio Di Bello, Claudio Marcocci, Enio Martino, and Fausto Bogazzi

Objective

The primary objective of this study is to identify the predictors of comorbidities and major adverse cardiovascular events (MACE) that can develop after diagnosis of acromegaly. The role of therapy for acromegaly in the event of such complications was also evaluated.

Design and methods

Retrospective cohort study was conducted on 200 consecutive acromegalic patients in a tertiary referral center. The following outcomes were evaluated: diabetes, hypertension and MACE. Each patient was included in the analysis of a specific outcome, unless they were affected when acromegaly was diagnosed, and further classified as follows: (i) in remission after adenomectomy (Hx), (ii) controlled by somatostatin analogues (SSA) (SSAc) or (iii) not controlled by SSA (SSAnc). Data were evaluated using Cox regression analysis.

Results

After diagnosis of acromegaly, diabetes occurred in 40.8% of patients. The SSAnc group had a three-fold higher risk of diabetes (HR: 3.32, P = 0.006), whereas the SSAc group had a 1.4-fold higher risk of diabetes (HR: 1.43, P = 0.38) compared with the Hx group. Hypertension occurred in 35.5% of patients, after diagnosis. The determinants of hypertension were age (HR: 1.06, P = 0.01) and BMI (HR: 1.05, P = 0.01). MACE occurred in 11.8% of patients, after diagnosis. Age (HR: 1.09, P = 0.005) and smoking habit (HR: 5.95, P = 0.01) were predictors of MACE. Conversely, therapy for acromegaly did not influence hypertension or MACE.

Conclusion

After diagnosis of acromegaly, control of the disease (irrespective of the type of treatment) and lifestyle are predictors of comorbidities and major adverse cardiovascular events.

Free access

Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma?

Filomena Cetani, Elena Ambrogini, Paolo Viacava, Elena Pardi, Giovanni Fanelli, Antonio Giuseppe Naccarato, Simona Borsari, Monica Lemmi, Piero Berti, Paolo Miccoli, Aldo Pinchera, and Claudio Marcocci

Objective: HRPT2 gene mutations are associated with parathyroid carcinomas, and absence of parafibromin immunoreactivity has been suggested as a diagnostic marker of malignancy. The aim of our study was to extend parafibromin studies in a series of benign and malignant parathyroid tumors and cross-validate the results of immunohistochemistry with those of HRPT2 analysis.

Design and patients: We performed parafibromin and cyclin D1 immunostaining and HRPT2 gene analysis using loss of heterozygosity studies and sequencing analysis in parathyroid specimens from 11 patients with carcinoma (eleven primary tumors, one skin, and four lung metastases), 22 with sporadic adenomas, and 4 with atypical adenomas.

Results: Ten out of eleven parathyroid cancers were negative for parafibromin staining and showed HRPT2 gene abnormalities. The remaining sample was negative for immunostaining and genetic analyses. All but one sporadic adenomas showed parafibromin immunoreactivity and no HRPT2 gene abnormalities. The sample with negative immunostaining carried an HRPT2 mutation. Two atypical adenomas were positive and two negative with parafibromin staining. No HRPT2 abnormalities were found in these samples. Cyclin D1 expression was heterogeneous and there was no relationship between expression/expression level of cyclin D1 and parafibromin expression.

Conclusions: We have shown that negative parafibromin staining is almost invariably associated with HRPT2 mutations and confirm that loss of parafibromin staining strongly predicts parathyroid malignancy. In clinical practice, these tests could be particularly useful in the subset of parathyroid tumors with equivocal histological examination. However, their diagnostic value in this setting remains to be proven.

Free access

Hypercalcemia due to CYP24A1 mutations: a systematic descriptive review

Daniele Cappellani, Alessandro Brancatella, Riccardo Morganti, Simona Borsari, Fulvia Baldinotti, Maria Adelaide Caligo, Martin Kaufmann, Glenville Jones, Claudio Marcocci, and Filomena Cetani

Background and objectives

CYP24A1 encodes a 24-hydroxylase involved in vitamin D catabolism, whose loss-of-function results in vitamin D-dependent hypercalcemia. Since the identification of CYP24A1 variants as a cause of idiopathic infantile hypercalcemia, a large body of literature has emerged indicating heterogeneity in penetrance, symptoms, biochemistry, and treatments. The objectives of the present research work were to investigate the clinical heterogeneity of the disease, the possibility of a relevant phenotype for monoallelic carriers, and to compare the hypocalcemic effect of the available therapies.

Methods

Two reviewers searched different databases for studies published between the identification of CYP24A1 variants and December 31, 2020. Eligible studies included clinical trials and reports describing carriers of CYP24A1 variants.

Results

Fifty eligible studies were identified, accounting for 221 patients. Genetic data were retrieved and allele frequencies were calculated. Acute hypercalcemia was the typical presentation during the first year of life (76%, P = 0.0005), and nephrocalcinosis was more frequent in infancy (P < 0.0001). Pregnancy was associated with symptomatic hypercalcemia in 81.8% and high rates of obstetric complications. Monoallelic carriers displayed significant rates of nephrolithiasis (19.4%), nephrocalcinosis (4.9%), and symptomatic hypercalcemia (5.6%).

Conclusions

CYP24A1 loss-of-function results in an age-dependent phenotype, which can be exacerbated by triggering factors, such as pregnancy. Although biallelic carriers present more significant clinical and biochemical features, monoallelic carriers have an increased risk of calcium-related conditions. The highly variable tested therapeutic approaches did not allow to draw conclusions on preferable therapeutic regime.

Free access

Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy: a questionnaire survey among members of the European Thyroid Association

Claudio Marcocci, Torquil Watt, Maria Antonietta Altea, Ase Krogh Rasmussen, Ulla Feldt-Rasmussen, Jacques Orgiazzi, Luigi Bartalena, and for the European Group of Graves' Orbitopathy (EUGOGO)

Objective

The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO).

Design

A questionnaire-based survey among members of the European Thyroid Association (ETA) who treat GO.

Results

A response was obtained from 128 ETA members of which 115 used GC therapy for GO. The majority of respondents (83/115, 72%) used intravenous (i.v.) GC, with a relatively wide variety of therapeutic regimens. The cumulative dose of methylprednisolone ranged between 0.5 and 12 g (median 4.5 g) for i.v.GC and between 1.0 and 4.9 g (median 2.4 g) for oral GC. Adverse events were often reported during oral GCs (26/32, 81%); most side effects were non-severe, but ten respondents reported severe adverse events (hepatic, cardiovascular, and cerebrovascular complications), including two fatal cases, both receiving a total of 2.3 g prednisone. Adverse events were less common in i.v.GC (32/83 respondents, 39%), but mostly consisted of severe events, including seven fatal cases. All but one fatal event occurred in cumulative i.v.GC doses (>8 g) higher than those currently recommended.

Conclusions

GCs are preferentially administered i.v. for the treatment of GO in Europe. Both oral and i.v.GC may be associated with severe adverse effects, including fatal cases, which are more frequently reported in daily or alternate day i.v.GC. IvGC therapy should be undertaken in centers with appropriate expertise. Patients should be carefully examined for risk factors before treatment and monitored for side effects, which may be asymptomatic, both during and after treatment.

Free access

European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults

Jens Bollerslev, Lars Rejnmark, Claudio Marcocci, Dolores M Shoback, Antonio Sitges-Serra, Wim van Biesen, and Olaf M Dekkers

Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors.

Restricted access

TSH and biogenic amine signals in the regulation of thyroid function: Independent regulation by protein kinase C and G proteins

Evelyn F. Grollman, Elisabeth Bone, John Chan, Daniella Corda, Osamu Isozaki, Claudio Marcocci, Pilar Santisteban, and Leonard D. Kohn

The primary role of the thyroid cell is to synthesize and secrete the thyroid hormones, T3 and T4 (Dumont et al. 1971; Robbins et al. 1980). This must be accomplished in a regulated manner and despite a variable intake of iodine. This role must also be accomplished despite the fact that the synthesis and secretion of thyroid hormones involves numerous steps. These include 1) the uptake of iodide across the basal membrane of the cell in a scavanging and concentrative fashion; 2) efflux of iodide across the apical membrane into the follicular lumen of the thyroid follicle; 3) the synthesis of thyroglobulin and its vectorial transport to the site of iodide efflux; 4) iodination of thyroglobulin; 5) regulated storage of the iodinated thyroglobulin; 6) lysosomal targeting and biodegradation, of the iodinated thyroglobulin; and 7) ultimately, secretion of T3/T4 into the bloodstream, across the basal membrane

Free access

Identification and functional characterization of loss-of-function mutations of the calcium-sensing receptor in four Italian kindreds with familial hypocalciuric hypercalcemia

Filomena Cetani, Monica Lemmi, Davide Cervia, Simona Borsari, Luisella Cianferotti, Elena Pardi, Elena Ambrogini, Chiara Banti, Edward M Brown, Paola Bagnoli, Aldo Pinchera, and Claudio Marcocci

Objective

Identification and characterization of calcium-sensing receptor (CASR) mutations in four unrelated Italian kindreds with familial hypocalciuric hypercalcemia.

Design

Clinical evaluation and genetic analysis of CASR gene. Functional characterization of mutated CASRs.

Methods

Direct sequencing of CASR gene in genomic DNA. Studies of CASR-mediated increases in cytosolic calcium concentration [Ca2 +]i in CASR-transfected COS-7 cells in vitro.

Results

Four unreported heterozygous CASR mutations were identified, including three missense (H595Y, P748H, and C765W) and one splice site (IVS2+1G>C) mutation. The H595Y, P748H, and C765W mutant receptors, although expressed at normal levels on the cell surface, showed a reduced response in [Ca2 +]i relative to the wildtype (WT) CASR to increasing extracellular calcium concentrations. Cotransfection experiments showed that the H595Y and P748H mutants did not affect the apparent affinity of the WT CASR for calcium, suggesting that they do not exert a dominant-negative effect. On the other hand, the co-transfected C765W mutant decreased the maximum response of the WT CASR to calcium, suggesting that it may reduce the effective concentration of the normal CASR on the cell surface or impair its maximal signaling capacity.

Conclusions

Four CASR mutations were identified. The reduced functional responses to extracellular calcium and normal expression of the mutant receptors suggest that conformational changes account for altered CASR activity. Moreover, a reduced complement of normal CASRs in these heterozygous patients, perhaps combined with a mutant receptor-induced decrease in maximal activity of the WT receptor, may contribute to defective calcium-sensing in vivo.