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Open access

John Alexander and Dinesh Nagi

Summary

Primary hyperparathyroidism (PHPT) is a disease caused by overactive parathyroid glands with consequent hypercalcaemia. The main cause in 85–90% of the cases is the presence of a solitary parathyroid adenoma. The most common presentation is with asymptomatic hypercalcaemia diagnosed on routine biochemical testing. Although low serum phosphate levels are an associated finding in primary hyperparathyroidism, the diagnostic criteria for PHPT remain to be hypercalcaemia, high or inappropriately normal PTH and hypercalciuria. This case report presents a patient who presented with low phosphate levels without any other biochemical evidence of PHPT, who returned several years later with overt primary hyperparathyroidism. This report intends to raise interest among the medical fraternity whether there is a need to consider hypophosphataemia as an early sign of PHPT.

Learning points

  • Primary hyperparathyroidism is a relatively common condition with varying clinical and biochemical presentation.
  • The most common presentations still remain as an asymptomatic biochemical abnormality closely related to calcium, PTH and bone metabolism.
  • Not much attention is usually given to associated biochemical abnormalities, and hence they are usually less investigated.
  • Further research is needed to establish if patients need long-term monitoring when no obvious cause for isolated hypophosphataemia has been found.
Open access

Natassia Rodrigo, Diana Learoyd, and Sarah J Glastras

Summary

Hypercalcaemia in pregnancy is uncommon, with associated adverse obstetric and perinatal outcomes for both the mother and the fetus. Determination of causality is central to its management. Diagnostic imaging techniques are limited during pregnancy and the diagnosis is made more complex by physiological changes in calcium and vitamin D homeostasis in pregnancy. Further, therapeutic options are limited due to safety considerations for the pregnant woman and the developing foetus. Three cases of hypercalcaemia in pregnancy will be presented, highlighting the distinct aetiologies and management strategies for hypercalcaemia in pregnancy and the importance of early measurement of serum calcium in pregnancy screening.

Learning points

  • There are complex physiological changes in calcium balance in pregnancy, including increased calcium intestinal absorption and renal excretion.
  • Hypercalcaemia in pregnancy is uncommon but has important potential maternal and foetal complications, making a compelling argument for routine antenatal, calcium screening.
  • Identifying the cause of hypercalcaemia in pregnancy can be challenging due to the complex placental interplay in biochemical test interpretation and due to safety constraints restricting imaging and surgery.
  • Acute medical management of hypercalcaemia must be considered in the context of both maternal and foetal well-being, along with gestational age and specific consideration for the safety of the developing fetus in late gestation.
Open access

Seong Keat Cheah, Chad Ramese Bisambar, Deborah Pitfield, Olivier Giger, Rogier ten Hoopen, Jose-Ezequiel Martin, Graeme R Clark, Soo-Mi Park, Craig Parkinson, Benjamin G Challis, and Ruth T Casey

Summary

A 38-year-old female was identified as carrying a heterozygous pathogenic MEN1 variant (c.1304delG) through predictive genetic testing, following a diagnosis of familial hyperparathyroidism. Routine screening for parathyroid and pituitary disease was negative. However, cross-sectional imaging by CT revealed a 41 mm pancreatic tail mass. Biopsy via endoscopic ultrasound confirmed the lesion to be a well-differentiated (grade 1) pancreatic neuroendocrine tumour (pNET) with MIB1<1%. Biochemically, hyperinsulinaemic hypoglycaemia was confirmed following an overnight fast, which was subsequently managed by diet alone prior to definitive surgery. Pre-operative work-up with octreotide SPECT CT demonstrated avid tracer uptake in the pancreatic lesion and, unexpectedly, a focal area of uptake in the left breast. Further investigation, and subsequent mastectomy, confirmed ductal carcinoma in situ pT2 (23 mm) grade 1, N0 (ER positive; HER2 negative). Following mastectomy, our patient underwent a successful distal pancreatectomy to resect the pNET. Loss of heterozygosity (LOH) at the MEN1 locus was found in both the breast tumour and pNET, thereby in keeping with a 'two-hit' hypothesis of oncogenesis, a suggestive but non-definitive clue for causation. To obtain further support for a causative relationship between MEN1 and breast cancer, we undertook a detailed review of the published literature which overall supports the notion that breast cancer is a MEN1-related malignancy that presents at a younger age and histologically, is typically of ductal subtype. Currently, clinical guidance regarding breast cancer surveillance in MEN1 does not exist and further research is required to establish a clinical and cost-effective surveillance strategy).

Learning points

  • We describe a case of pNET and breast cancer diagnosed at a young age of 38 years in a patient who is heterozygous for a pathogenic MEN1 variant. Loss of the wild-type allele was seen in both breast tissue and pNET specimen.
  • Breast cancer may be an under-recognised MEN1-associated malignancy that presents at a younger age than in the general population with a relative risk of 2–3.
  • Further research is required to determine the cost-effectiveness of breast cancer surveillance approach at a younger age in MEN1 patients relative to the general population .
Open access

Ben Wilkinson, Sharifah Faradila Wan Muhamad Hatta, Andrew Garnham, and Harit N Buch

Summary

Primary hyperparathyroidism requires a surgical approach to achieve a long-term cure. However, post-surgical recurrence significantly complicates the management of this condition. A number of causes for recurrent disease are well understood and several diagnostic modalities exist to localise the culprit parathyroid adenoma although none of them is efficacious in localisation of the recurrent lesion. In this case report, we highlight a novel causative mechanism and describe a unique diagnostic sequence that enabled curative treatment to be delivered.

Learning points

  • In the case described herein, we describe a novel location for a parathyroid adenoma causing recurrent PHPT. The case elucidates well the difficulties presented by such cases in terms of surgical planning and show the utility of PVS in such cases. Based on this case, we make the following recommendations:
  • Meticulous care must be taken to prevent seeding of adenomatous tissue during primary excision.
  • To consider the use of PVS in patients with discordant imaging in the setting of recurrent/persistent PHPT as a method to localise the causative adenoma.
  • Same day PVS and surgery is a viable option for patients who either represent an anaesthetic risk or who are extremely anxious about the prospect of two separate procedures.
  • Disordered calcium homeostasis is an important but forgotten cause of dysphagia which can be extremely debilitating for affected patients.
Open access

Dalal Ali, Patrick Divilly, Ruth Prichard, Dermot O’Toole, Donal O’Shea, and Rachel K Crowley

Summary

Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited endocrine disorder with a high rate of penetrance. The incidence of MEN1 is 1/30,000 in the general population; however, it is quite rare for a patient to present for medical attention with MEN1 for the first time in pregnancy. Primary hyperparathyroidism (PHPT) is one of the most common features of MEN1. The incidence of PHPT occurring in pregnancy is 1%. Despite advances in the medical, surgical and obstetric care over the years, management of this condition during pregnancy may be challenging. It can be difficult to identify pregnant women with PHPT requiring intervention and to monitor safely. Hypercalcemia can result in significant maternal and fetal adverse outcomes including: miscarriage, intrauterine growth restriction, preterm delivery, neonatal hypocalcaemia, pre-eclampsia and maternal nephrolithiasis. Herein, we present a case study of a lady with a strong family history of MEN1, who was biochemically proven to have PHPT and evidence of Zollinger Ellison Syndrome (ZE) on endoscopy. This patient delayed her assisted pregnancy plans for in vitro fertilization (IVF) until completion of the MEN1 workup; nevertheless, she spontaneously achieved an unplanned pregnancy. As a result, she required intervention with parathyroidectomy in the second trimester of her pregnancy as her calcium level continued to rise. This case study highlights the workup, follow up and management of MEN1 presenting with PHPT and ZE in pregnancy.

Learning points

  • Women of childbearing age who are suspected to have a diagnosis of primary hyperparathyroidism ideally should have genetic testing and avoid pregnancy until definitive plans are in place.
  • Zollinger Ellison syndrome in pregnancy means off-label use of high dose of proton pump inhibitors (PPI). Use of PPI in pregnancy is considered to be safe based on retrospective studies. Omeprazole, however, is FDA class C drug because of lack of large prospective studies or large case series during pregnancy.
  • Calcium supplements in the form of calcium carbonate must be converted to calcium chloride by gastric acid in order to be absorbed, however, patients rendered achlorhydric as a result of PPI use will have impaired absorption of calcium. Therefore, use of calcium citrate might be considered a better option in this case.
Open access

Joana Lima Ferreira, Francisco Simões de Carvalho, Ana Paula Marques, and Rosa Maria Príncipe

Summary

Autoimmune polyglandular syndrome type 1 (APS-1) is a very rare autoimmune entity, accounting for about 400 cases reported worldwide. It is characterized by the presence of at least two of three cardinal components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison’s disease. It typically manifests in childhood with CMC and years later with hypoparathyroidism. A 50-year-old man was referred to the Endocrinology outpatient clinic due to irregular follow-up of primary hypoparathyroidism diagnosed at age 7. Previous analysis reported frequent fluctuations of calcium and phosphate levels and persistent hypercalciuria. He presented several comorbidities, including bilateral cataracts, other ocular disorders, transient alopecia and chronic gastritis. Due to weight loss, fatigue, gastrointestinal complaints and the findings at objective examination, Addison’s disease and CMC were investigated and confirmed. Antifungal therapy and hormonal replacement were started with evident clinical improvement. Regarding hypoparathyroidism, calcium-phosphate product decreased and other extraskeletal calcifications were diagnosed, such as nephrolithiasis and in basal ganglia. Further evaluation by genetic analysis revealed homozygosity for a frameshift mutation considered to be a pathogenic variant. It was reported only in two Asian siblings in compound heterozygosity. This case highlights the broad phenotypic spectrum of APS-1 and the significative intra-familial phenotype variability. A complete clinical history taking and high index of suspicion allowed the diagnosis of this rare entity. This case clarifies the need for regular long-term follow-up. In the specific case of hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex.

Learning points:

  • Autoimmune polyglandular syndrome type 1 (APS-1) is a deeply heterogeneous genetic entity with a broad spectrum of clinical manifestations and a significant intra-family phenotypic variability.
  • Early diagnosis of APS-1 is challenging but clinically relevant, as endocrine and non-endocrine manifestations may occur during its natural history.
  • APS-1 should be considered in cases of acquired hypoparathyroidism, and even more so with manifestations with early onset, family history and consanguinity.
  • APS-1 diagnosis needs a high index of suspicion. Key information such as all the comorbidities and family aspects would never be valued in the absence of a complete clinical history taking.
  • Especially in hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex and is not a matter of simply approaching individually each condition.
  • Regular long-term monitoring of APS-1 is essential. Intercalary contact by phone calls benefits the control of the disease and the management of complications.
Open access

Annabel S Jones, Annabelle M Warren, Leon A Bach, and Shoshana Sztal-Mazer

Summary

Conventional treatment of hypoparathyroidism relies on oral calcium and calcitriol. Challenges in managing post-parathyroid- and post-thyroidectomy hypocalcaemia in patients with a history of bariatric surgery and malabsorption have been described, but postoperative management of bariatric surgery in patients with established hypoparathyroidism has not. We report the case of a 46-year-old woman who underwent elective sleeve gastrectomy on a background of post-surgical hypoparathyroidism and hypothyroidism. Multiple gastric perforations necessitated an emergency Roux-en-Y gastric bypass. She was transferred to a tertiary ICU and remained nil orally for 4 days, whereupon her ionised calcium level was 0.78 mmol/L (1.11–1.28 mmol/L). Continuous intravenous calcium infusion was required. She remained nil orally for 6 months due to abdominal sepsis and the need for multiple debridements. Intravenous calcium gluconate 4.4 mmol 8 hourly was continued and intravenous calcitriol twice weekly was added. Euthyroidism was achieved with intravenous levothyroxine. Maintaining normocalcaemia was fraught with difficulties in a patient with pre-existing surgical hypoparathyroidism, where oral replacement was impossible. The challenges in managing hypoparathyroidism in the setting of impaired enteral absorption are discussed with analysis of the cost and availability of parenteral treatments.

Learning points:

  • Management of hypoparathyroidism is complicated when gastrointestinal absorption is impaired.
  • Careful consideration should be given before bariatric surgery in patients with pre-existing hypoparathyroidism, due to potential difficulty in managing hypocalcaemia, which is exacerbated when complications occur.
  • While oral treatment of hypoparathyroidism is cheap and relatively simple, available parenteral options can carry significant cost and necessitate a more complicated dosing schedule.
  • International guidelines for the management of hypoparathyroidism recommend the use of PTH analogues where large doses of calcium and calcitriol are required, including in gastrointestinal disorders with malabsorption.
  • Approval of subcutaneous recombinant PTH for hypoparathyroidism in Australia will alter future management.
Open access

Satyanarayana V Sagi, Hareesh Joshi, Jamie Trotman, Terence Elsey, Ashwini Swamy, Jeyanthy Rajkanna, Nazir A Bhat, Firas J S Haddadin, Samson O Oyibo, and Soo-Mi Park

Summary

Familial hypocalciuric hypercalcaemia (FHH) is a dominantly inherited, lifelong benign disorder characterised by asymptomatic hypercalcaemia, relative hypocalciuria and variable parathyroid hormone levels. It is caused by loss-of-function pathogenic variants in the calcium-sensing receptor (CASR) gene. Primary hyperparathyroidism (PHPT) is characterised by variable hypercalcaemia in the context of non-suppressed parathyroid hormone levels. Unlike patients with FHH, patients with severe hypercalcaemia due to PHPT are usually symptomatic and are at risk of end-organ damage affecting the kidneys, bone, heart, gastrointestinal system and CNS. Surgical resection of the offending parathyroid gland(s) is the treatment of choice for PHPT, while dietary adjustment and reassurance is the mainstay of management for patients with FHH. The occurrence of both FHH and primary hyperparathyroidism (PHPT) in the same patient has been described. We report an interesting case of FHH due to a novel CASR variant confirmed in a mother and her two daughters and the possible coexistence of FHH and PHPT in the mother, highlighting the challenges involved in diagnosis and management.

Learning points:

  • Familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism (PHPT) can coexist in the same patient.
  • Urinary calcium creatinine clearance ratio can play a role in distinguishing between PHPT and FHH.
  • Genetic testing should be considered in managing patients with PHPT and FHH where the benefit may extend to the wider family.
  • Family segregation studies can play an important role in the reclassification of variants of uncertain significance.
  • Parathyroidectomy has no benefit in patients with FHH and therefore, it is important to exclude FHH prior to considering surgery.
  • For patients with coexisting FHH and PHPT, parathyroidectomy will reduce the risk of complications from the severe hypercalcaemia associated with PHPT.
Open access

Thien Vinh Luong, Lars Rejnmark, Anne Kirstine Arveschoug, Peter Iversen, and Lars Rolighed

Multiple endocrine neoplasia 1 (MEN1) is a rare genetic syndrome characterized by the manifestation of tumors in endocrine glands most often in the parathyroid gland (PG). Treatment may involve several parathyroidectomies (PTX), especially in young patients, which increases the risk of postoperative complications. We present a 16-year-old patient with a family history of MEN1 syndrome. The patient started to show biochemical signs of hyperparathyroidism (HPT) and hypercalcemia at the age of 10. One and a half years later a PTX was successfully performed with removal of the two left PGs. However, a rise in plasma parathyroid hormone and ionized calcium was observed 4 years later. Preoperative noninvasive imaging with 99mTc-sestamibi scintigraphy showed no definitive parathyroid adenoma. A 11C-methionine position emission tomography combined with MRI (MET-PET/MRI) was then performed and detected a focus posterior to the lower part of the right thyroid lobe. Intraoperative angiography with fluorescence and indocyanine green dye was used to assess the vascularization of the remaining PGs. The lower right PG was removed. The patient was discharged with normalized biochemical values and without postoperative complications. Recurrence of primary HPT is frequent in MEN1 patients which often necessitates repeated operations. Our case report showed that the use of advanced noninvasive preoperative imaging techniques and intraoperative fluorescent imaging are valuable tools and should be taken into consideration in selected cases to avoid postoperative complications. To our knowledge, this is the first case where MET-PET/MRI has been used to detect parathyroid pathology.

Learning points:

  • MEN1 patients will develop parathyroid disease, which eventually will lead to surgical treatment with removal of the pathological glands.
  • Preoperatively usage of MRI combined with PET tracers such as 11C-methionine and 18F-Fluorocholine are able to detect parathyroid pathology with a higher sensitivity than conventional imaging.
  • Techniques using intraoperatively angiography with fluorescence and florescent dyes allow surgeons to verify the vascularization of each parathyroid gland.
  • Optimization of noninvasive preoperative imaging techniques and intraoperative fluorescent imaging are valuable tools and should be taken into consideration when performing PTX consecutively in the same patient to avoid postoperative complications.
Open access

Jane J Tellam, Ghusoon Abdulrasool, and Louise C H Ciin

Summary

Distinguishing primary hyperparathyroidism (PHPT) from familial hypocalciuric hypercalcaemia (FHH) can be challenging. Currently, 24-h urinary calcium is used to differentiate between the two conditions in vitamin D replete patients, with urinary calcium creatinine clearance ratio (UCCR) <0.01 suggestive of FHH and >0.02 supportive of PHPT. A 26-year-old Caucasian gentleman presented with recurrent mild hypercalcaemia and inappropriately normal parathyroid hormone (PTH) following previous parathyroidectomy 3 years prior. He had symptoms of fatigue and light-headedness. He did not have any other symptoms of hypercalcaemia. His previous evaluation appeared to be consistent with PHPT as evidenced by hypercalcaemia with inappropriately normal PTH and UCCR of 0.0118 (borderline low using guidelines of >0.01 consistent with PHPT). He underwent parathyroidectomy and three parathyroid glands were removed. His calcium briefly normalised after surgery, but rose again to pre-surgery levels within 3 months. Subsequently, he presented to our centre and repeated investigations showed 24-h urinary calcium of 4.6 mmol/day and UCCR of 0.0081 which prompted assessment for FHH. His calcium-sensing receptor (CASR) gene was sequenced and a rare inactivating variant was detected. This variant was described once previously in the literature. His mother was also confirmed to have mild hypercalcaemia with hypocalciuria and, on further enquiry, had the same CASR variant. The CASR variant was classified as likely pathogenic and is consistent with the diagnosis of FHH. This case highlights the challenges in differentiating FHH from PHPT. Accurate diagnosis is vital to prevent unnecessary surgical intervention in the FHH population and is not always straightforward.

Learning points:

  • Distinguishing FHH from PHPT with co-existing vitamin D deficiency is difficult as this can mimic FHH. Therefore, ensure patients are vitamin D replete prior to performing 24-h urinary calcium collection.
  • Individuals with borderline UCCR could have either FHH or PHPT. Consider performing CASR gene sequencing for UCCR between 0.01 and 0.02.
  • Parathyroid imaging is not required for making the diagnosis of PHPT. It is performed when surgery is considered after confirming the diagnosis of PHPT.