Diagnosis and Treatment > Medication > Bisphosphonates
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Centre for Endocrine and Diabetes Sciences, University Hospital of Wales, Cardiff, UK
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Search for other papers by Mohamed Adlan in
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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:
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The differential diagnosis of hypercalcaemia is sometimes a challenge.
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Diagnosis may require multidisciplinary expertise and multiple and invasive investigations.
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There may be several disparate causes for hypercalcaemia, although one usually predominates.
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Maintaining ‘body image’ even with the use of harmful drugs may be an overpowering emotion despite counselling about their dangers.
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Search for other papers by Catherine Cho in
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Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
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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:
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Milk-alkali syndrome is an often unrecognised cause for hypercalcaemia, but is the third most common cause of admission for hypercalcaemia.
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Calcium ingestion leading to MAS can occur at intakes as low as 1.0–1.5 g per day in those with risk factors.
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Early recognition of this syndrome can avoid the use of calcium-lowering therapy such as bisphosphonates which can precipitate hypocalcaemia.
Search for other papers by Nirusha Arnold in
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Search for other papers by Victor O’Toole in
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Search for other papers by Tien Huynh in
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Search for other papers by Howard C Smith in
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Search for other papers by Catherine Luxford in
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Westmead Teaching Hospital, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia
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Summary
Parathyroid-independent hypercalcaemia of pregnancy, due to biallelic loss of function of the P450 enzyme CYP24A1, the principal inactivator of 1,25(OH)2D results in hypervitaminosis D, hypercalcaemia and hypercalciuria. We report two cases of this disorder, with intractable hypercalcaemia, one occurring during gestation and into the postpartum, and the other in the postpartum period. Case 1, a 47-year-old woman with a twin pregnancy conceived by embryo transfer, presented with hypercalcaemia at 23 weeks gestation with subnormal serum parathyroid hormone (PTH) and normal serum 25-OH D levels. She was admitted to hospital at 31 weeks gestation with pregnancy-induced hypertension, gestational diabetes and increasing hypercalcaemia. Caesarean section at 34 weeks gestation delivered two healthy females weighing 2.13 kg and 2.51 kg. At delivery, the patient’s serum calcium level was 2.90 mmol/L. Postpartum severe hypercalcaemia was treated successfully with Denosumab 60 mg SCI, given on two occasions. CYP24A1 testing revealed she was compound heterozygous for pathogenic variants c.427_429delGAA, (p.Glu143del) and c.1186C>T, (p.Arg396Trp). Case 2, a 36-year-old woman presented 4 days after the delivery of healthy twins with dyspnoea, bradycardia, severe headaches, hypertension and generalized tonic-clonic seizures after an uneventful pregnancy. She was hypercalcaemic with a suppressed PTH, normal 25(OH)D, and elevated 1,25(OH)2D levels. Her symptoms partially responded to i.v. saline and corticosteroids in the short term but bisphosphonates such as Pamidronate and Zoledronic acid did not result in sustained improvement. Denosumab 120 mg SCI successfully treated the hypercalcaemia which resolved completely 2 months post-partum. CYP24A1 testing revealed she was homozygous for the pathogenic variant c.427_429delGAA, (p.Glu143del).
Learning points:
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Hypercalcaemia in pregnancy can be associated with considerable morbidity with few options available for management.
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In non-PTH-related hypercalcaemia the diagnosis of CYP24A1 deficiency should be considered.
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Making a definitive diagnosis of CYP24A1 deficiency by genetic testing delays the diagnosis, while the availability of serum 24,25-dihydroxyvitamin D (24,25(OH)2D) will expedite a diagnosis.
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In pregnant women with CYP24A1 deficiency hypercalcaemia can worsen in the post-partum period and is more likely to occur with twin pregnancies but generally resolves within 2–3 months.
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Therapeutic alternatives are limited in pregnancy and their effectiveness is short-lived and mostly ineffective. Denosumab used in both our patients after delivery was the most effective agent normalizing calcium and may have benefit as a long-term therapeutic agent in preventing complications in patients with CYP24A1 deficiency.
Search for other papers by Mona Abouzaid in
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Search for other papers by Ahmed Al-Sharefi in
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Department of Endocrinology and Diabetes, North Tees and Hartlepool Hospitals NHS Foundation Trust, Hartlepool, UK
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Summary
An 82-year-old male with a proven diagnosis of primary hyperparathyroidism (PHPT) was found to have bilateral changes in the fundi during a routine eye examination which were consistent with SC. In this report, we discuss the link between SC and PHPT and question the need for prospective observational studies to establish the true association between these conditions. Though screening PHPT patients for SC might not be justified/warranted given the benign course of the latter, patients with SC need to be assessed for PHPT, as the former may be the first clue to an underlying treatable systemic disease.
Learning points:
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Sclerochoroidal calcifications (SCs), though rare and harmless, could be associated with an underlying systemic disease, such as primary hyperparathyroidism (PHPT).
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Biochemical screening for hypercalcaemia is a simple, cheap and widely available tool that could facilitate an identification of undiagnosed PHPT in patients with SC.
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A joint care by endocrinologists and ophthalmologists is warranted for those patients, as thorough investigations and long-term follow-up plans are crucial.
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
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Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
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Department of General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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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:
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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.
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PHPT and hypercalcaemia of malignancy, account for the majority of clinical presentations of hypercalcaemia.
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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.
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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.
Search for other papers by Michal Barabas in
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IMED Biotech Unit, Clinical Discovery Unit, AstraZeneca, Cambridge, UK
Search for other papers by Benjamin G Challis in
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Summary
A 67-year-old woman presented with a generalised rash associated with weight loss and resting tachycardia. She had a recent diagnosis of diabetes mellitus. Biochemical evaluation revealed elevated levels of circulating glucagon and chromogranin B. Cross-sectional imaging demonstrated a pancreatic lesion and liver metastases, which were octreotide-avid. Biopsy of the liver lesion confirmed a diagnosis of well-differentiated grade 2 pancreatic neuroendocrine tumour, consistent with metastatic glucagonoma. Serial echocardiography commenced 4 years before this diagnosis demonstrated a progressive left ventricular dilatation and dysfunction in the absence of ischaemia, suggestive of glucagonoma-associated dilated cardiomyopathy. Given the severity of the cardiac impairment, surgical management was considered inappropriate and somatostatin analogue therapy was initiated, affecting clinical and biochemical improvement. Serial cross-sectional imaging demonstrated stable disease 2 years after diagnosis. Left ventricular dysfunction persisted, however, despite somatostatin analogue therapy and optimal medical management of cardiac failure. In contrast to previous reports, the case we describe demonstrates that chronic hyperglucagonaemia may lead to irreversible left ventricular compromise. Management of glucagonoma therefore requires careful and serial evaluation of cardiac status.
Learning points:
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In rare cases, glucagonoma may present with cardiac failure as the dominant feature. Significant cardiac impairment may occur in the absence of other features of glucagonoma syndrome due to subclinical chronic hyperglucagonaemia.
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A diagnosis of glucagonoma should be considered in patients with non-ischaemic cardiomyopathy, particularly those with other features of glucagonoma syndrome.
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Cardiac impairment due to glucagonoma may not respond to somatostatin analogue therapy, even in the context of biochemical improvement.
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All patients with a new diagnosis of glucagonoma should be assessed clinically for evidence of cardiac failure and, if present, a baseline transthoracic echocardiogram should be performed. In the presence of cardiac impairment these patients should be managed by an experienced cardiologist.
Search for other papers by C Kamath in
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Section of Endocrinology, Department of Medicine, Ysbyty Ystrad Fawr, Caerphilly, UK
Search for other papers by L D Premawardhana in
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Summary
Thymic enlargement (TE) in Graves’ disease (GD) is often diagnosed incidentally when chest imaging is done for unrelated reasons. This is becoming more common as the frequency of chest imaging increases. There are currently no clear guidelines for managing TE in GD. Subject 1 is a 36-year-old female who presented with weight loss, increased thirst and passage of urine and postural symptoms. Investigations confirmed GD, non-PTH-dependent hypercalcaemia and Addison’s disease (AD). CT scans to exclude underlying malignancy showed TE but normal viscera. A diagnosis of hypercalcaemia due to GD and AD was made. Subject 2, a 52-year-old female, was investigated for recurrent chest infections, haemoptysis and weight loss. CT thorax to exclude chest malignancy, showed TE. Planned thoracotomy was postponed when investigations confirmed GD. Subject 3 is a 47-year-old female who presented with breathlessness, chest pain and shakiness. Investigations confirmed T3 toxicosis due to GD. A CT pulmonary angiogram to exclude pulmonary embolism showed TE. The CT appearances in all three subjects were consistent with benign TE. These subjects were given appropriate endocrine treatment only (without biopsy or thymectomy) as CT appearances showed the following appearances of benign TE – arrowhead shape, straight regular margins, absence of calcification and cyst formation and radiodensity equal to surrounding muscle. Furthermore, interval scans confirmed thymic regression of over 60% in 6 months after endocrine control. In subjects with CT appearances consistent with benign TE, a conservative policy with interval CT scans at 6 months after endocrine control will prevent inappropriate surgical intervention.
Learning points:
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Chest imaging is common in modern clinical practice and incidental anterior mediastinal abnormalities are therefore diagnosed frequently.
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Thymic enlargement (TE) associated with Graves’ disease (GD) is occasionally seen in view of the above.
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There is no validated strategy to manage TE in GD at present.
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However, CT (or MRI) scan features of the thymus may help characterise benign TE, and such subjects do not require thymic biopsy or surgery at presentation.
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In them, an expectant ‘wait and see’ policy is recommended with GD treatment only, as the thymus will show significant regression 6 months after endocrine control.
Monash Centre for Health Research and Implementation, Clayton, Australia
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Hudson Institute of Medical Research, Clayton, Australia
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Hudson Institute of Medical Research, Clayton, Australia
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Hudson Institute of Medical Research, Clayton, Australia
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Monash Centre for Health Research and Implementation, Clayton, Australia
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Hudson Institute of Medical Research, Clayton, Australia
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Summary
The association between type 1 diabetes mellitus (T1DM) and bone health has garnered interest over the years. Fracture risk is known to be increased in individuals with T1DM, although bone health assessment is not often performed in the clinical setting. We describe the case of a 21-year-old male with longstanding T1DM with multilevel vertebral fractures on imaging, after presenting with acute back pain without apparent trauma. Dual-energy X-ray absorptiometry (DXA) revealed significantly reduced bone mineral density at the lumbar spine and femoral neck. Extensive investigations for other secondary or genetic causes of osteoporosis were unremarkable, apart from moderate vitamin D deficiency. High-resolution peripheral quantitative computed tomography and bone biospy revealed significant alterations of trabecular bone microarchitecture. It later transpired that the patient had sustained vertebral fractures secondary to unrecognised nocturnal hypoglycaemic seizures. Intravenous zoledronic acid was administered for secondary fracture prevention. Despite anti-resorptive therapy, the patient sustained a new vertebral fracture after experiencing another hypoglycaemic seizure in his sleep. Bone health in T1DM is complex and not well understood. There are significant challenges in the assessment and management of osteoporosis in T1DM, particularly in young adults, where fracture prediction tools have not been validated. Clinicians should be aware of hypoglycaemia as a significant risk factor for fracture in patients with T1DM.
Learning points:
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Type 1 diabetes mellitus (T1DM) is a secondary cause of osteoporosis, characterised by reduced bone mass and disturbed bone microarchitecture.
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Hypoglycaemic seizures generate sufficient compression forces along the thoracic column and can cause fractures in individuals with compromised bone quality.
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Unrecognised hypoglycaemic seizures should be considered in patients with T1DM presenting with fractures without a history of trauma.
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Patients with T1DM have increased fracture risk and risk factors should be addressed. Evaluation of bone microarchitecture may provide further insights into mechanisms of fracture in T1DM.
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Further research is needed to guide the optimal screening and management of bone health in patients with T1DM.
Search for other papers by N Chelaghma in
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Summary
Hypogonadotrophic hypogonadism is due to impaired or reduced gonadotrophin secretion from the pituitary gland. In the absence of any anatomical or functional lesions of the pituitary or hypothalamic gland, the hypogonadotrophic hypogonadism is referred to as idiopathic hypogonadotrophic hypogonadism (IHH). We present a case of a young lady born to consanguineous parents who was found to have IHH due to a rare gene mutation.
Learning points:
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The genetic basis of a majority of cases of IHH remains unknown.
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IHH can have different clinical endocrine manifestations.
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Patients can present late to the healthcare service because of unawareness and stigmata associated with the clinical features.
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Family members of affected individuals can be affected to varying degrees.
Department of Medicine, Endocrinology Division, Lebanese University, Hadath, Lebanon
Endocrinology Department, Rafic Hariri University Hospital, Beirut, Lebanon
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Department of Medicine, Endocrinology Division, Lebanese University, Hadath, Lebanon
Endocrinology Department, Mount Lebanon Hospital, Beirut, Lebanon
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Department of Radiology, Beirut Governmental University Hospital, Beirut, Lebanon
Diagnostic Radiology, Radiology Department
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Department of Medicine, Endocrinology Division, Lebanese University, Hadath, Lebanon
Clinical Endocrinology, Endocrinology Department, Rafic Hariri University Hospital, Beirut, Lebanon
Search for other papers by Mohamad Souheil El Rawas in
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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:
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Learning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.
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Understanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.
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Providing the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes.
