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Open access

Eseoghene Ifie, Samson O Oyibo, Hareesh Joshi and Olugbenro O Akintade

Summary

Iron (ferric carboxymaltose) infusion therapy is used to treat severe iron deficiency which is not responding to the first-line oral iron therapy. However, it can also cause severe renal wasting of phosphate resulting in severe hypophosphataemia in some patients. Despite the growing number of case reports, this side effect is not well known to healthcare professionals. The product labelling information sheet does mention that hypophosphataemia can be a side effect, but also says that this side effect is usually transient and asymptomatic. We report a challenging case of a patient who developed severe, symptomatic and prolonged hypophosphataemia after an intravenous iron infusion for severe iron deficiency.

Learning points:

  • Clinicians prescribing ferric carboxymaltose (Ferinject®) should be aware of the common side effect of hypophosphataemia, which could be mild, moderate or severe.
  • Patients receiving iron infusion should be educated concerning this potential side effect.
  • Pre-existing vitamin D deficiency, low calcium levels, low phosphate levels or raised parathyroid hormone levels may be risk factors, and these should be evaluated and corrected before administering intravenous iron.
  • Patients may require phosphate and vitamin D replacement along with monitoring for a long period after iron infusion-induced hypophosphataemia.
  • Every incident should be reported to the designated body so that the true prevalence and management thereof can be ascertained.
Open access

Andrew R Tang, Laura E Hinz, Aneal Khan and Gregory A Kline

Summary

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, autosomal recessive disorder caused by mutations in the SLC34A3 gene that encodes the renal sodium-dependent phosphate cotransporter 2c (NaPi-IIc). It may present as intermittent mild hypercalcemia which may attract initial diagnostic attention but appreciation of concomitant hypophosphatemia is critical for consideration of the necessary diagnostic approach. A 21-year-old woman was assessed by adult endocrinology for low bone mass. She initially presented age two with short stature, nephrocalcinosis and mild intermittent hypercalcemia with hypercalciuria. She had no evidence of medullary sponge kidney or Fanconi syndrome and no bone deformities, pain or fractures. She had recurrent episodes of nephrolithiasis. In childhood, she was treated with hydrochlorothiazide to reduce urinary calcium. Upon review of prior investigations, she had persistent hypophosphatemia with phosphaturia, low PTH and a high-normal calcitriol. A diagnosis of HHRH was suspected and genetic testing confirmed a homozygous c.1483G>A (p.G495R) missense mutation of the SLC34A3 gene. She was started on oral phosphate replacement which normalized her serum phosphate, serum calcium and urine calcium levels over the subsequent 5 years. HHRH is an autosomal recessive condition that causes decreased renal reabsorption of phosphate, leading to hyperphosphaturia, hypophosphatemia and PTH-independent hypercalcemia due to the physiologic increase in calcitriol which also promotes hypercalciuria. Classically, patients present in childhood with bone pain, vitamin D-independent rickets and growth delay. This case of a SLC34A3 mutation illustrates the importance of investigating chronic hypophosphatemia even in the presence of other more common electrolyte abnormalities.

Learning points:

  • Hypophosphatemia is an important diagnostic clue that should not be ignored, even in the face of more common electrolyte disorders.
  • HHRH is a cause of PTH-independent hypophosphatemia that may also show hypercalcemia.
  • HHRH is a cause of hypophosphatemic nephrocalcinosis that should not be treated with calcitriol, unlike other congenital phosphate wasting syndromes.
  • Some congenital phosphate wasting disorders may not present until adolescence or early adulthood.
Open access

Aisling McCarthy, Sophie Howarth, Serena Khoo, Julia Hale, Sue Oddy, David Halsall, Brian Fish, Sashi Mariathasan, Katrina Andrews, Samson O Oyibo, Manjula Samyraju, Katarzyna Gajewska-Knapik, Soo-Mi Park, Diana Wood, Carla Moran and Ruth T Casey

Summary

Primary hyperparathyroidism (PHPT) is characterised by the overproduction of parathyroid hormone (PTH) due to parathyroid hyperplasia, adenoma or carcinoma and results in hypercalcaemia and a raised or inappropriately normal PTH. Symptoms of hypercalcaemia occur in 20% of patients and include fatigue, nausea, constipation, depression, renal impairment and cardiac arrythmias. In the most severe cases, uraemia, coma or cardiac arrest can result. Primary hyperparathyroidism in pregnancy is rare, with a reported incidence of 1%. Maternal and fetal/neonatal complications are estimated to occur in 67 and 80% of untreated cases respectively. Maternal complications include nephrolithiasis, pancreatitis, hyperemesis gravidarum, pre-eclampsia and hypercalcemic crises. Fetal complications include intrauterine growth restriction; preterm delivery and a three to five-fold increased risk of miscarriage. There is a direct relationship between the degree of severity of hypercalcaemia and miscarriage risk, with miscarriage being more common in those patients with a serum calcium greater than 2.85 mmol/L. Neonatal complications include hypocalcemia. Herein, we present a case series of three women who were diagnosed with primary hyperparathyroidism in pregnancy. Case 1 was diagnosed with multiple endocrine neoplasia type 1 (MEN1) in pregnancy and required a bilateral neck exploration and subtotal parathyroidectomy in the second trimester of her pregnancy due to symptomatic severe hypercalcaemia. Both case 2 and case 3 were diagnosed with primary hyperparathyroidism due to a parathyroid adenoma and required a unilateral parathyroidectomy in the second trimester. This case series highlights the work-up and the tailored management approach to patients with primary hyperparathyroidism in pregnancy.

Learning points:

  • Primary hyperparathyroidism in pregnancy is associated with a high incidence of associated maternal fetal and neonatal complications directly proportionate to degree of maternal serum calcium levels.
  • Parathyroidectomy is the definitive treatment for primary hyperparathyroidism in pregnancy and was used in the management of all three cases in this series. It is recommended when serum calcium is persistently greater than 2.75 mmol/L and or for the management of maternal or fetal complications of hypercalcaemia. Surgical management, when necessary is ideally performed in the second trimester.
  • Primary hyperparathyroidism is genetically determined in ~10% of cases, where the likelihood is increased in those under 40 years, where there is relevant family history and those with other related endocrinopathies. Genetic testing is a useful diagnostic adjunct and can guide treatment and management options for patients diagnosed with primary hyperparathyroidism in pregnancy, as described in case 1 in this series, who was diagnosed with MEN1 syndrome.
  • Women of reproductive age with primary hyperparathyroidism need to be informed of the risks and complications associated with primary hyperparathyroidism in pregnancy and pregnancy should be deferred and or avoided until curative surgery has been performed and calcium levels have normalised.
Open access

Peter Novodvorsky, Ziad Hussein, Muhammad Fahad Arshad, Ahmed Iqbal, Malee Fernando, Alia Munir and Sabapathy P Balasubramanian

Summary

Spontaneous remission of primary hyperparathyroidism (PHPT) due to necrosis and haemorrhage of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’ is a very rare, but previously described phenomenon. Patients usually undergo parathyroidectomy or remain under close clinical and biochemical surveillance. We report two cases of parathyroid auto-infarction diagnosed in the same tertiary centre; one managed surgically and the other conservatively up to the present time. Case #1 was a 51-year old man with PHPT (adjusted (adj.) calcium: 3.11 mmol/L (reference range (RR): 2.20–2.60 mmol/L), parathyroid hormone (PTH) 26.9 pmol/L (RR: 1.6–6.9 pmol/L) and urine calcium excretion consistent with PHPT) referred for parathyroidectomy. Repeat biochemistry 4 weeks later at the surgical clinic showed normal adj. calcium (2.43 mmol/L) and reduced PTH. Serial ultrasound imaging demonstrated reduction in size of the parathyroid lesion from 33 to 17 mm. Twenty months later, following recurrence of hypercalcaemia, he underwent neck exploration and resection of an enlarged right inferior parathyroid gland. Histology revealed increased fibrosis and haemosiderin deposits in the parathyroid lesion in keeping with auto-infarction. Case #2 was a 54-year-old lady admitted with severe hypercalcaemia (adj. calcium: 4.58 mmol/L, PTH 51.6 pmol/L (RR: 1.6–6.9 pmol/L)) and severe vitamin D deficiency. She was treated with intravenous fluids and pamidronate and 8 days later developed symptomatic hypocalcaemia (1.88 mmol/L) with dramatic decrease of PTH (17.6 pmol/L). MRI of the neck showed a 44 mm large cystic parathyroid lesion. To date, (18 months later), she has remained normocalcaemic.

Learning points:

  • Primary hyperparathyroidism (PHPT) is characterised by excess parathyroid hormone (PTH) secretion arising mostly from one or more autonomously functioning parathyroid adenomas (up to 85%), diffuse parathyroid hyperplasia (<15%) and in 1–2% of cases from parathyroid carcinoma.
  • PHPT and hypercalcaemia of malignancy, account for the majority of clinical presentations of hypercalcaemia.
  • Spontaneous remission of PHPT due to necrosis, haemorrhage and infarction of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’, ‘auto-parathyroidectomy’ or ‘parathyroid apoplexy’ is a very rare in clinical practice but has been previously reported in the literature.
  • In most cases, patients with parathyroid auto-infarction undergo parathyroidectomy. Those who are managed conservatively need to remain under close clinical and biochemical surveillance long-term as in most cases PHPT recurs, sometimes several years after auto-infarction.
Open access

Bidhya Timilsina, Niranjan Tachamo, Prem Raj Parajuli and Ilan Gabriely

Summary

A 74-year-old woman presented with progressive lethargy, confusion, poor appetite and abdominal pain. She was found to have non-PTH-mediated severe hypercalcemia with renal failure and metabolic alkalosis. Extensive workup for hypercalcemia to rule out alternate etiology was unrevealing. Upon further questioning, she was taking excess calcium carbonate (Tums) for her worsening heartburn. She was diagnosed with milk-alkali syndrome (MAS). Her hypercalcemia and alkalosis recovered completely with aggressive hydration along with improvement in her renal function. High index of suspicion should be maintained and history of drug and supplements, especially calcium ingestion, should be routinely asked in patients presenting with hypercalcemia to timely diagnose MAS and prevent unnecessary tests and treatments.

Learning points:

  • Suspect milk-alkali syndrome in patients with hypercalcemia, metabolic alkalosis and renal failure, especially in context of ingestion of excess calcium-containing supplements.
  • Careful history of over-the-counter medications, supplements and diet is crucial to diagnose milk-alkali syndrome.
  • Milk-alkali syndrome may cause severe hypercalcemia in up to 25–30% of cases.
Open access

Benjamin Kwan, Bernard Champion, Steven Boyages, Craig F Munns, Roderick Clifton-Bligh, Catherine Luxford and Bronwyn Crawford

Summary

Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members.

Learning points:

  • ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia.
  • In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients.
  • CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members.
  • Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.
Open access

Cheuk-Lik Wong, Chun-Kit Fok and Vicki Ho-Kee Tam

Summary

We report a case of elderly Chinese lady with neurofibromatosis type-1 presenting with longstanding palpitation, paroxysmal hypertension and osteoporosis. Biochemical testing showed mild hypercalcaemia with non-suppressed parathyroid hormone level suggestive of primary hyperparathyroidism, and mildly elevated urinary fractionated normetanephrine and plasma-free normetanephrine pointing to a catecholamine-secreting pheochromocytoma/paraganglioma. Further scintigraphic investigation revealed evidence of a solitary parathyroid adenoma causing primary hyperparathyroidism and a left pheochromocytoma. Resection of the parathyroid adenoma and pheochromocytoma resulted in normalization of biochemical abnormalities and hypertension. The rare concurrence of primary hyperparathyroidism and pheochromocytoma in neurofibromatosis type-1 is discussed.

Learning points:

  • All NF-1 patients who have symptoms suggestive of a pheochromocytoma/paraganglioma (PPGL), even remotely, should undergo biochemical testing.
  • The initial biochemical tests of choice for PPGL in NF-1 are either plasma-free metanephrines or urinary fractionated metanephrines. Any elevations of metanephrines should be carefully evaluated for the presence of PPGLs in NF-1 patients.
  • Primary hyperparathyroidism (PHPT) is described in subjects with NF-1. Due to the lack of epidemiological and functional studies, their association is yet to be substantiated. Meanwhile, PHPT may further exacerbate the metabolic bone defect in these patients and should be treated when present according to published guidelines.
  • Coexistence of PPGL and PHPT can occur in subjects with NF-1, mimicking multiple endocrine neoplasia type 2 (MEN2).
Open access

Carine Ghassan Richa, Khadija Jamal Saad, Ali Khaled Chaaban and Mohamad Souheil El Rawas

Summary

The objective of the study is to report a case of acute pancreatitis secondary to hypercalcemia induced by primary hyperparathyroidism in a pregnant woman at the end of the first trimester. The case included a 32-year-old woman who was diagnosed with acute pancreatitis and severe hypercalcemia refractory to many regimens of medical therapy in the first trimester of pregnancy. She was successfully treated with parathyroidectomy in the early second trimester with complete resolution of hypercalcemia and pancreatitis. Neonatal course was unremarkable. To our best knowledge, this is a rare case when primary hyperparathyroidism and its complications are diagnosed in the first trimester of pregnancy. In conclusion, primary hyperparathyroidism is a rare life-threatening condition to the fetus and mother especially when associated with complications such as pancreatitis. Early therapeutic intervention is important to reduce the morbidity and mortality. Parathyroidectomy performed in the second trimester can be the only solution.

Learning points:

  • Learning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.
  • Understanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.
  • Providing the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes.
Open access

Caroline Bachmeier, Chirag Patel, Peter Kanowski and Kunwarjit Sangla

Summary

Primary hyperparathyroidism (PH) is a common endocrine abnormality and may occur as part of a genetic syndrome. Inactivating mutations of the tumour suppressor gene CDC73 have been identified as accounting for a large percentage of hyperparathyroidism-jaw tumour syndrome (HPT-JT) cases and to a lesser degree account for familial isolated hyperparathyroidism (FIHP) cases. Reports of CDC73 whole gene deletions are exceedingly rare. We report the case of a 39 year-old woman with PH secondary to a parathyroid adenoma associated with a large chromosomal deletion (2.5 Mb) encompassing the entire CDC73 gene detected years after parathyroidectomy. This case highlights the necessity to screen young patients with hyperparathyroidism for an underlying genetic aetiology. It also demonstrates that molecular testing for this disorder should contain techniques that can detect large deletions.

Learning points:

  • Necessity of genetic screening for young people with hyperparathyroidism.
  • Importance of screening for large, including whole gene CDC73 deletions.
  • Surveillance for patients with CDC73 gene mutations includes regular calcium and parathyroid hormone levels, dental assessments and imaging for uterine and renal tumours.
Open access

Elda Kara, Elisa Della Valle, Sara De Vincentis, Vincenzo Rochira and Bruno Madeo

Summary

Spontaneous or fine-needle aspiration (FNAB)-induced remission of primary hyperparathyroidism (PHPT) may occur, especially for cystic lesions. However, the disease generally relapses over a short time period. We present a case of PHPT due to an enlarged hyperfunctioning parathyroid that underwent long-term (almost 9 years) clinical and ultrasonographic remission after the disappearance of the lesion following ultrasound (US)-assisted FNAB. A 67-year-old woman with PHPT underwent biochemical and US examinations that confirmed the diagnosis and showed a lesion suggestive for parathyroid adenoma or hyperplasia. US-FNAB of the lesion confirmed its parathyroid nature by means of elevated levels of parathyroid hormone within the needle washing fluid. At the second visit, the patient referred slight neck swelling that resolved spontaneously in the days after the US-FNAB. At subsequent follow-up, the enlarged parathyroid was not found; it was visible neither with US nor with magnetic resonance imaging. Biochemical remission persists after 9 years. This is the first reported case of cure of PHPT after US-FNAB performed on a hyperfunctioning parathyroid resulting in its complete disappearance over a period of 9 years of negative biochemical and ultrasonographic follow-up.

Learning points:

  • Spontaneous or fine-needle aspiration-induced remission of primary hyperparathyroidism can occur.
  • Both circumstances may present disease relapse over a variable time period, but definite remission is also possible even though long-term periodic follow-up should be performed.
  • Parathyroid damage should be ruled out in case of neck symptomatology after parathyroid fine-needle aspiration or spontaneous symptomatology in patients with history of primary hyperparathyroidism.