Abstract
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.
Background
Primary hyperparathyroidism, drugs and malignant disease are common causes of hypercalcaemia in secondary care. However, granulomatous disorders, immobility, familial hypocalciuric hypercalcaemia (FHH) and vitamin D excess are also responsible occasionally (1, 2, 3). Inflammatory myositis and rhabdomyolysis may occasionally cause hypercalcaemia severe enough to require treatment. In this situation, calcium phosphate complexes laid down during the oliguric phase of acute kidney injury (AKI) are thought to be released during the polyuric phase of AKI causing significant hypercalcaemia (4). Subjects who present with these and other rarer causes of hypercalcaemia, either alone or in combination, are often a diagnostic and management dilemma. Multiple, complicated and sometimes invasive investigations may need to be done in order to diagnose a cause for their hypercalcaemia and to direct therapy. Their management often requires multidisciplinary expertise.
Case presentation
A 53-year-old retired fire-fighter, who was an obsessive body builder, presented with severe constipation of many weeks’ duration. He had no osmotic symptoms, bone or muscle pains, and denied other symptoms. He volunteered no erectile dysfunction or loss of libido and passed normal quantities of urine without discoloration or symptoms of renal dysfunction. His appetite and weight were normal, and he took lansoprazole and tamsulosin only without over-the-counter medications. However, he admitted to the use of growth hormone (GH) 2 IU/day and testosterone (T) 350 mg/day on a ‘6-weeks on and 4-weeks off’ regime for over 20 years. He did not smoke or consume alcohol. There was no significant family history and he had no children of his own.
On examination, he appeared well, had mild ankle oedema, but no clubbing, jaundice or lymphadenopathy. He had hard globular masses under both axillae which were difficult to characterize. His limb girdle muscles were bulky, well developed and non-tender. Muscle power in all muscle groups was normal. Systems examination was unremarkable and, in particular, there were no skin abnormalities, hepatosplenomegaly or palpable abdominal masses.
Investigation
Investigations at presentation and subsequently showed the following –
Treatment
At his first admission the following diagnoses were made – (1) likely non-PTH mediated severe hypercalcaemia likely due to acute myositis and rhabdomyolysis; (2) acute kidney injury (AKI) with significant proteinuria complicating chronic kidney disease. Subsequent investigations pointed to contributions to hypercalcaemia from (1) likely primary hyperparathyroidism and (2) hypervitaminosis A. Acute myositis and rhabdomyolysis were of unknown aetiology but likely iatrogenic, non-traumatic or idiopathic.
He was rapidly rehydrated with normal saline according to protocols for hypercalcaemia and AKI and i.v. pamidronate 60 mg was given. Subsequently, prednisolone (30 mg/day and reducing) and mycophenolate mofetil (500 mg increased to 1 g bd) were given for acute inflammatory myositis. A trial of cinacalcet was tried as it was felt that primary hyperparathyroidism could be contributing to his hypercalcaemia – his PTH was not completely supressed despite markedly raised calcium levels, that is, 2 mmol/L (1.6–7.2). The cinacalcet helped lower his calcium levels when he was compliant. He improved symptomatically and metabolically – serum calcium (2.39 mmol/L), eGFR (26) and CK (2505 U/L) in a few months. Despite counselling, he continued to take GH and T on a ‘6-weeks on/4-weeks off’ regime, as he considered these vital for maintaining his body image.
Outcome and follow-up
His subsequent clinical course was punctuated by repeated admissions for hypercalcaemia and renal deterioration with partial and incomplete recovery on treatment (Table 1). He also presented with an episode of left ventricular failure and was given furosemide 40 mg and bisoprolol 1.25 mg. Subsequently, cinacalcet was commenced – 30 mg bd reduced to 30 mg/day. Mycophenolate was stopped due to intolerance and prednisolone was stopped by the patient without consultation. He continued also to be on tamsulosin for prostatic hypertrophy. Despite regular multidisciplinary review, he passed away suddenly. Post-mortem examination revealed myocardial infarction as the cause of death.
Biochemical indices during acute admissions.
Admission | eGFR | Creatinine | CK | Calcium |
---|---|---|---|---|
1 | 19 | 298 | 7952 | 3.66 |
2 | 11 | 418 | 4362 | 3.34 |
3 | 16 | 346 | 3.44 | |
4 | 15 | 362 | 5421 | 3.10 |
5 | 13 | 424 | 1858 | 2.88 |
Biochemical indices during 5 acute admissions demonstrating gradual renal deterioration and improvement in hypercalcaemia and myositis.
Discussion
We have presented a 53-year-old amateur body builder on long-term intermittent GH and T self-medication, who presented with severe symptomatic hypercalcaemia complicating acute inflammatory myositis and rhabdomyolysis. He also had AKI (with chronic kidney disease) and significant proteinuria due to FSGS.
We encountered significant diagnostic and management challenges in dealing with him.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent was obtained from the patient/patient’s mother for publication of this case report.
Author contribution statement
All authors were involved in the diagnosis and management of this subject, either as part of the direct care team or as part of the multidisciplinary team. R R, L D P and M A wrote this manuscript (with contributions from the rest), which was finally approved by all authors.
References
- 1↑
Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia.BMJ 2015 350 h2723. (https://doi.org/10.1136/bmj.h2723)
- 2↑
Coltzman D. Nonparathyroid hypercalemia. Frontiers of Hormone Research 2019 51 77–90. (https://doi.org/10.1159/000491040)
- 3↑
Silva BC, Cusano NE, Bilezakian JP. Primary hyperparathyroidism. Best Practice and Research: Clinical Endocrinology and Metabolism 2018 32 593–607. (https://doi.org/10.1016/j.beem.2018.09.004)
- 4↑
Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, Płudowski P, Glenville Jones. Vitamin D toxicity: a clinical perspective. Frontiers in Endocrinology 2018 9 550. (https://doi.org/10.3389/fendo.2018.00550.2018)
- 5↑
Cetari F, Saponaro F, Borsari S, Marccoci C. Familial and hereditary forms of primary hyperparathyroidism. Frontiers of Hormone Research 2019 51 40–51. (https://doi.org/10.1159/000491037)
- 6↑
Gracia-Maldonado G, Castro-García RJ. Endocrinological disorders related to the medical use of lithium. A narative review. Revista Colombiana de Psiquiatria 2019 48 35–43. (https://doi.org/10.1016/j.rcp.2017.01.003)
- 7↑
Mirza ZB, Hu S, Amorosa LF. Bone scintigraphy of severe hypercalcaemia following simvastatin induced rhabdomyolysis. Clinical Cases in Mineral and Bone Metabolism 2016 13 257–261. (https://doi.org/10.11138/ccmbm/2016.13.3.257)
- 8↑
Wang FY, NG CY, Wu J, Kuo KL, Chang YY, Kuo TT. Acquired perforating calcific collagenosis in a drug addict with rhabdomyolysis and transient hypercalcaemia. Journal of Cutaneous Pathology 2019 46 84–87. (https://doi.org/10.1111/cup.13371)
- 9↑
Boyce BF, Fell GS, Elder HY, Junor BJ, Elliot HL, Beastall G, Fogelman I, Boyle IT. Hypercalcaemic osteomalacia due to aluminium toxicity. Lancet 1982 2 1009–1013. (https://doi.org/10.1016/s0140-6736(82)90049-6)
- 10↑
Jose N, Kurian GP. Schimidt syndrome: an unusual cause of severe hypercalcemia. Journal of Clinical and Diagnostic Research 2016 10 OD21-2. (https://doi.org/10.7860/JCDR/2016/16770.7783)
- 11↑
Ragno A, Pepe J, Badiali D, Minisola S, Romagnoli E, Severi C, D’Erasmo E. Chronic constipation in hypercalcaemic patients with primary hyperparathyroidism. European Review for Medical and Pharmacological Sciences 2012 16 884–889.