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Open access

Ravikumar Ravindran, Justyna Witczak, Suhani Bahl, Lakdasa D K E Premawardhana, and Mohamed Adlan

Summary

A 53-year-old man who used growth hormone (GH), anabolic steroids and testosterone (T) for over 20 years presented with severe constipation and hypercalcaemia. He had benign prostatic hyperplasia and renal stones but no significant family history. Investigations showed – (1) corrected calcium (reference range) 3.66 mmol/L (2.2–2.6), phosphate 1.39 mmol/L (0.80–1.50), and PTH 2 pmol/L (1.6–7.2); (2) urea 21.9 mmol/L (2.5–7.8), creatinine 319 mmol/L (58–110), eGFR 18 mL/min (>90), and urine analysis (protein 4+, glucose 4+, red cells 2+); (3) creatine kinase 7952 U/L (40–320), positive anti Jo-1, and Ro-52 antibodies; (4) vitamin D 46 nmol/L (30–50), vitamin D3 29 pmol/L (55–139), vitamin A 4.65 mmol/L (1.10–2.60), and normal protein electrophoresis; (5) normal CT thorax, abdomen and pelvis and MRI of muscles showed ‘inflammation’, myositis and calcification; (6) biopsy of thigh muscles showed active myositis, chronic myopathic changes and mineral deposition and of the kidneys showed positive CD3 and CD45, focal segmental glomerulosclerosis and hypercalcaemic tubular changes; and (7) echocardiography showed left ventricular hypertrophy (likely medications and myositis contributing), aortic stenosis and an ejection fraction of 44%, and MRI confirmed these with possible right coronary artery disease. Hypercalcaemia was possibly multifactorial – (1) calcium release following myositis, rhabdomyolysis and acute kidney injury; (2) possible primary hyperparathyroidism (a low but detectable PTH); and (3) hypervitaminosis A. He was hydrated and given pamidronate, mycophenolate and prednisolone. Following initial biochemical and clinical improvement, he had multiple subsequent admissions for hypercalcaemia and renal deterioration. He continued taking GH and T despite counselling but died suddenly of a myocardial infarction.

Learning points:

  • The differential diagnosis of hypercalcaemia is sometimes a challenge.

  • Diagnosis may require multidisciplinary expertise and multiple and invasive investigations.

  • There may be several disparate causes for hypercalcaemia, although one usually predominates.

  • Maintaining ‘body image’ even with the use of harmful drugs may be an overpowering emotion despite counselling about their dangers.

Open access

Mawson Wang, Catherine Cho, Callum Gray, Thora Y Chai, Ruhaida Daud, and Matthew Luttrell

Summary

We report the case of a 65-year-old female who presented with symptomatic hypercalcaemia (corrected calcium of 4.57 mmol/L) with confusion, myalgias and abdominal discomfort. She had a concomitant metabolic alkalosis (pH 7.46, HCO3 - 40 mmol/L, pCO2 54.6 mmHg). A history of significant Quick-Eze use (a calcium carbonate based antacid) for abdominal discomfort, for 2 weeks prior to presentation, suggested a diagnosis of milk-alkali syndrome (MAS). Further investigations did not demonstrate malignancy or primary hyperparathyroidism. Following management with i.v. fluid rehydration and a single dose of i.v. bisphosphonate, she developed symptomatic hypocalcaemia requiring oral and parenteral calcium replacement. She was discharged from the hospital with stable biochemistry on follow-up. This case demonstrates the importance of a detailed history in the diagnosis of severe hypercalcaemia, with MAS representing the third most common cause of hypercalcaemia. We discuss its pathophysiology and clinical importance, which can often present with severe hypercalcaemia that can respond precipitously to calcium-lowering therapy.

Learning points:

  • Milk-alkali syndrome is an often unrecognised cause for hypercalcaemia, but is the third most common cause of admission for hypercalcaemia.

  • Calcium ingestion leading to MAS can occur at intakes as low as 1.0–1.5 g per day in those with risk factors.

  • Early recognition of this syndrome can avoid the use of calcium-lowering therapy such as bisphosphonates which can precipitate hypocalcaemia.

Open access

S Hamidi, S Mottard, M J Berthiaume, J Doyon, M J Bégin, and L Bondaz

Summary

Brown tumors (BTs) are expansile osteolytic lesions complicating severe primary hyperparathyroidism (PHPT). Clinical, radiological and histological features of BTs share many similarities with other giant cell-containing lesions of the bone, which can make their diagnosis challenging. We report the case of a 32-year-old man in whom an aggressive osteolytic lesion of the iliac crest was initially diagnosed as a giant cell tumor by biopsy. The patient was scheduled for surgical curettage, with a course of neoadjuvant denosumab. Routine biochemical workup prior to denosumab administration incidentally revealed high serum calcium levels. The patient was diagnosed with PHPT and a parathyroid adenoma was identified. In light of these findings, histological slices of the iliac lesion were reviewed and diagnosis of a BT was confirmed. Follow-up CT-scans performed 2 and 7 months after parathyroidectomy showed regression and re-ossification of the bone lesion. The aim of this case report is to underline the importance of distinguishing BTs from other giant cell-containing lesions of the bone and to highlight the relevance of measuring serum calcium as part of the initial evaluation of osteolytic bone lesions. This can have a major impact on patients’ management and can prevent unnecessary invasive surgical interventions.

Learning points:

  • Although rare, brown tumors should always be considered in the differential diagnosis of osteolytic giant cell-containing bone lesions.

  • Among giant cell-containing lesions of the bone, the main differential diagnoses of brown tumors are giant cell tumors and aneurysmal bone cysts.

  • Clinical, radiological and histological characteristics can be non-discriminating between brown tumors and giant cell tumors. One of the best ways to distinguish these two diagnoses appears to be through biochemical workup.

  • Differentiating brown tumors from giant cell tumors and aneurysmal bone cysts is crucial in order to ensure better patient care and prevent unnecessary morbid surgical interventions.

Open access

Aisha A Tepede, James Welch, Maya Lee, Adel Mandl, Sunita K Agarwal, Naris Nilubol, Dhaval Patel, Craig Cochran, William F Simonds, Lee S Weinstein, Abhishek Jha, Corina Millo, Karel Pacak, and Jenny E Blau

Summary

Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients.

Learning points:

  • 18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients.

  • Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions.

  • MEN1 is implicated in the tumorigenesis of PHEO in this patient.

Open access

Florence Gunawan, Elizabeth George, and Mark Kotowicz

Summary

Denosumab is a fully human MAB that acts as a potent anti-resorptive by inhibiting activation of osteoclasts by inhibiting the receptor activator of nuclear factor-kappa B (RANK) ligand. Hypocalcaemia has been reported as one of the serious adverse sequelae of use of denosumab. We present a case of refractory hypocalcaemia following administration of a single dose of denosumab in a patient with metastatic castrate-resistant prostate cancer. The patient’s serum calcium and vitamin D concentrations and renal function were normal prior to denosumab administration. Serum alkaline phosphatase (ALP) level was however elevated pre-morbidly consistent with known bone metastases. The patient was treated with high-dose oral and IV calcium without any appreciable response in serum calcium. During his 30-day hospital admission, he demonstrated disease progression with development of new liver metastases and bone marrow involvement. Normocalcaemia was not achieved despite 1 month of aggressive therapy. Given the patient was asymptomatic and prognosis guarded, he was eventually discharged for ongoing supportive care under the palliative care team.

Learning points:

  • Denosumab is a potent anti-resorptive therapy and hypocalcaemia is one of the known adverse effects.

  • Serum calcium and vitamin D concentrations must be replete prior to administration of denosumab to reduce the risk of hypocalcaemia.

  • Denosumab has been proven to be more effective than zoledronic acid in preventing skeletal-related adverse effects in patients with metastatic castrate-resistant prostate cancer.

Open access

Joanna Prokop, João Estorninho, Sara Marote, Teresa Sabino, Aida Botelho de Sousa, Eduardo Silva, and Ana Agapito

Summary

POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes) is a rare multisystemic disease. Clinical presentation is variable, the only mandatory criteria being polyneuropathy and monoclonal gammapathy in association with one major and one minor criterion. Primary adrenal insufficiency is rarely reported. We describe a case of a 33-year-old patient, in whom the presenting symptoms were mandibular mass, chronic sensory-motor peripheral polyneuropathy and adrenal insufficiency. The laboratory evaluation revealed thrombocytosis, severe hyperkalemia with normal renal function, normal protein electrophoresis and negative serum immunofixation for monoclonal protein. Endocrinologic laboratory work-up confirmed Addison’s disease and revealed subclinical primary hypothyroidism. Thoracic abdominal CT showed hepatosplenomegaly, multiple sclerotic lesions in thoracic vertebra and ribs. The histopathologic examination of the mandibular mass was nondiagnostic. Bone marrow biopsy revealed plasma cell dyscrasia and confirmed POEMS syndrome. Axillary lymphadenopathy biopsy: Castleman’s disease. Gluco-mineralocorticoid substitution and levothyroxine therapy were started with clinical improvement. Autologous hematopoietic cell transplantation (HCT) was planned, cyclophosphamide induction was started. Meanwhile the patient suffered two ischemic strokes which resulted in aphasia and hemiparesis. Cerebral angiography revealed vascular lesions compatible with vasculitis and stenosis of two cerebral arteries. The patient deceased 14 months after the diagnosis. The young age at presentation, multiplicity of manifestations and difficulties in investigation along with the absence of serum monoclonal protein made the diagnosis challenging. We report this case to highlight the need to consider POEMS syndrome in differential diagnosis of peripheral neuropathy in association with endocrine abnormalities even in young patients.

Learning points:

  • POEMS syndrome is considered a ‘low tumor burden disease’ and the monoclonal protein in 15% of cases is not found by immunofixation.

  • Neuropathy is the dominant characteristic of POEMS syndrome and it is peripheral, ascending, symmetric and affecting both sensation and motor function.

  • Endocrinopathies are a frequent feature of POEMS syndrome, but the cause is unknown.

  • The most common endocrinopathies are hypogonadism, primary hypothyroidism and abnormalities in glucose metabolism.

  • There is no standard therapy; however, patients with disseminated bone marrow involvement are treated with chemotherapy with or without HCT.

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

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

Maria P Yavropoulou, Efstathios Chronopoulos, George Trovas, Emmanouil Avramidis, Francesca Marta Elli, Giovanna Mantovani, Pantelis Zebekakis, and John G Yovos

Summary

Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the parathyroid hormone. Type 1A (PHP1A), which is the most common variant, also include developmental and skeletal defects named as Albright hereditary osteodystrophy (AHO). We present two cases, a 54- and a 33-year-old male diagnosed with PHP who were referred to us for persistently high levels of serum calcitonin. AHO and multinodular goitre were present in the 54-year-old male, while the second patient was free of skeletal deformities and his thyroid gland was of normal size and without nodular appearance. We performed GNAS molecular analysis (methylation status and copy number analysis by MS-MLPA) in genomic DNA samples for both patients. The analysis revealed a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1, in the patient with the clinical diagnosis of PHP1A. This amino acid change appears to be in accordance with the clinical diagnosis of the patient. The genomic DNA analysis of the second patient revealed the presence of the recurrent 3-kb deletion affecting the imprinting control region localised in the STX16 region associated with the loss of methylation (LOM) at the GNAS A/B differentially methylated region and consistent with the diagnosis of an autosomal dominant form of PHP type 1B (PHP1B). In conclusion, hypercalcitoninaemia may be encountered in PHP1A and PHP1B even in the absence of thyroid pathology.

Learning points:

  • We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A.

  • Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling.

  • GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.

Open access

Alejandro García-Castaño, Leire Madariaga, Sharona Azriel, Gustavo Pérez de Nanclares, Idoia Martínez de LaPiscina, Rosa Martínez, Inés Urrutia, Aníbal Aguayo, Sonia Gaztambide, and Luis Castaño

Summary

Familial hypocalciuric hypercalcemia type I is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the CASR gene and is characterized by moderately elevated serum calcium concentrations, low urinary calcium excretion and inappropriately normal or mildly elevated parathyroid hormone (PTH) concentrations. We performed a clinical and genetic characterization of one patient suspected of familial hypocalciuric hypercalcemia type I. Patient presented persistent hypercalcemia with normal PTH and 25-hydroxyvitamin D levels. The CASR was screened for mutations by PCR followed by direct Sanger sequencing and, in order to detect large deletions or duplications, multiplex ligation-dependent probe amplification (MLPA) was used. One large deletion of 973 nucleotides in heterozygous state (c.1733-255_2450del) was detected. This is the first large deletion detected by the MLPA technique in the CASR gene.

Learning points:

  • Molecular studies are important to confirm the differential diagnosis of FHH from primary hyperparathyroidism.

  • Large deletions or duplications in the CASR gene can be detected by the MLPA technique.

  • Understanding the functional impact of the mutations is critical for leading pharmacological research and could facilitate the therapy of patients.