Abstract
Albeit still rare, hypercalcaemia has been linked to pulmonary oedema in solid organ malignancy and chronic renal failure. However to date, there is only one case report linking pulmonary oedema to hypercalcaemia secondary to primary hyperparathyroidism.
Case presentation
A 60-year-old male presented to the emergency department with a history of confusion and collapse. Investigations revealed initial serum calcium of over 5 mmol/L. He subsequently developed widespread bilateral chest infiltrates with increasing oxygen requirements and an acute kidney injury. On day 9, continuous haemodiafiltration was commenced; however, hypercalcaemia proved resistant to maximal therapy. His initial parathyroid hormone (PTH) level measured 371 ng/L, and an ultrasound of his neck revealed a 2 × 2.5 cm parathyroid mass in the inferior neck. An acute parathyroidectomy was performed following which his chest infiltrates resolved and serum calcium levels returned to within normal range.
Conclusions
This case highlights primary hyperparathyroidism and the resulting hypercalcaemia as a sole cause for multi-organ failure in an otherwise well patient.
Keywords
Background
Parathyroid hormone is central in the tight control of serum calcium. In primary hyperparathyroidism, excessive release of PTH results in abnormally high serum calcium levels. Typical symptoms include muscle aches and weakness, gastrointestinal disturbance and confusion; however, the PTH molecule and increased circulating calcium can have a myriad of effects on organ physiology, precipitating the symptoms described in this case.
Case presentation
As 60-year-old Caucasian male who spoke little English presented initially with confusion and weakness. He collapsed on arrival at the emergency department. He had minimal significant medical history, taking valsartan and hydrothiazide for hypertension, as well as calcium supplements during the year prior to presentation. He was a non-smoker with minimal alcohol intake. He had been in the UK for two months at the time of presentation. He had no occupational exposure to pathogens or chemicals.
On admission to a local district general hospital, the serum calcium was found to be > 5 mmol/L and treated with a single dose of 90 mg intravenous pamidronate. An initial chest X-ray was normal although bilateral infiltrates were present two days later (Figure 1). A subsequent CT scan revealed evidence of bilateral nephritis, bilateral small renal calculi, as well as ill-defined opacifications bilaterally in the upper and middle lung fields, thought to be consistent with either underlying infective changes or fluid overload. Cardiomegaly with coronary artery calcification was also noted. Five days after initial presentation, he was transferred to a teaching hospital for ongoing nephrology input, whereby the admission calcium was 4.45 mmol/L despite having undergone haemodiafiltration for three days at the district general hospital. He was haemodynamically stable at this point, with a heart rate of 84/min, blood pressure of 158/70 mmHg, saturations of 99% on room air with no respiratory distress and he was apyrexial. Further imaging demonstrated diffuse pulmonary shadowing and a repeat CT scan showed progression of bilateral airspace consolidation of “unclear aetiology” widespread coronary artery calcification and multiple small bilateral renal calculi were again noted. Due to the radiographic changes in his chest, along with an initial white cell count of 15.78 × 109/L and CRP of 323 mg/L, he was treated concurrently for an atypical chest infection on the advice of the infectious disease and microbiology specialities. However, multiple blood and sputum cultures taken during the course of this admission all showed no growth of organisms. Vasculitic, atypical and tuberculosis screens were all negative.
Comparison of chest X-ray taken on admission (left) with a chest X-ray taken two days later (right) following development of widespread pulmonary infiltrates.
As a result of worsening renal function and resistant hypercalcaemia, haemodiafiltration was recommenced on day 7 following his initial presentation and he was admitted to intensive care on day 9 to facilitate this. During this time, serum calcium levels remained markedly elevated and creatinine levels peaked at 523 µmol/L. PTH levels were consistent with primary hyperparathyroidism (316 ng/L). A palpable nodule located in his neck was detected on examination and further investigation with ultrasound scan demonstrated a 2 × 2.5 cm hypoechoic mass lesion at the inferior pole of the left thyroid with foci of macrocalcification.
Over the following days, increasing confusion, resistant hypercalcaemia, and escalating oxygen requirements developed. An echocardiogram revealed mild to moderate concentric left ventricular hypertrophy with hyperdynamic left ventricular function and no valvular defects. This was in keeping with the clinical state of pulmonary oedema secondary to high output failure with a palpable thrill.
After seven further days of CVVHDF, the patient's serum calcium remained 3.7 mmol/L. Following MDT discussion, he underwent an acute parathyroidectomy on the consensus that despite aggressive medical management, there was limited improvement biochemically and definitive intervention necessitated removal of the underlying suspected pathology. The resolution of symptoms with a view to subsequent outpatient operative management was deemed unfeasible.
Within hours of surgery, his parathyroid hormone levels reduced to 92.1 ng/L, reducing further to 2.1 ng/L on day 1 post-operatively. Calcium levels also showed significant reduction over the following days, returning to within normal limits three days postoperatively. Renal function gradually improved following surgery and haemodiafiltration was safely discontinued seven days postoperatively (Figure 2). These clinical changes were accompanied with diminishing oxygen requirements and resolving confusion, facilitating discharge from intensive care two weeks later.
A graph showing adjusted serum calcium against renal function during time on intensive care. A postoperative acute kidney injury is noted which resolved with on-going renal replacement therapy and a continued decrease in adjusted serum calcium.
Histology confirmed parathyroid adenoma.
Discussion and conclusions
This case highlights the potential multi-system effect of hypercalcaemia on the respiratory, cardiovascular and renal systems. Numerous searches on PubMed revealed only one case report relating hypercalcaemia secondary to primary hyperparathyroidism with pulmonary oedema.
In this article, Mert et al. 1 report a case of a 72-year-old patient who presented with clinical and radiological pulmonary oedema due to hypercalcaemia. Further investigation revealed a parathyroid adenoma. Signs and symptoms settled once serum calcium was normalised via medical management. 1
A further letter was found dating back to 1974 linking hypercalcaemia to pulmonary oedema, postulating that calcium microdeposits may play a role. 2 It appears that most patients had other predisposing factors such as a primary malignancy or chronic renal failure. This theory is further described by Hsu and Chen 3 in their case series on neoplastic hypercalcaemia, which also describes an increase in endothelial permeability due to high calcium levels. This may be a precipitant in the development of this patients pulmonary oedema, especially when combined with hyperdynamic cardiac function. In vitro, raised nitrate/nitrite, free radicals, proinflammatory cytokines, procalcitonin and inducible nitric oxide synthase activity suggest that hypercalcaemia induces a sepsis-like syndrome. 4
Acute kidney injury is a more established complication of hypercalcaemia, for example in milk-alkali syndrome. However, overall, it remains a rare cause for renal failure. A recent review of patients requiring haemodiafiltration in a nephrology unit for the treatment of hypercalcaemic crisis, demonstrated only eight cases of acute kidney injury. 5
As described above, our patient had developed a hyperdynamic cardiac state with a palpable thrill, likely contributing to a degree of circulatory overload, increased diastolic pressure and pulmonary oedema. A review by Andersson et al. 6 found increasing evidence of pathological LVH in patients with primary hyperparathyroidism. It also highlighted PTH and PTHrP (PTH-related peptide) both share receptor affinity, and in vitro studies have demonstrated inotropic and chronotropic effects of PTHrP on cardiac tissue. Similarly, PTH increases intracellular calcium concentration in cardiomyocytes which promotes hypertrophy via the actions on the protein kinase C cascade. These in vitro findings have been supported in vivo. An increased prevalence of cardiac hypertrophy has been reported in patients with primary hyperparathyroidism, irrespective of hypertension, age and gender, and appears to be unrelated to biochemical or clinical disease severity. 6
Conclusion
We report a case of primary hyperparathyroidism and associated hypercalcaemia which resulted in multi-organ failure, affecting the respiratory, renal and cardiovascular systems. The severity of the disease may well be linked to a delay in presentation and delay in diagnosis due to interhospital transfer. Management of this case required the input of several specialities and the surgical intervention, with curative intent, was undertaken acutely as the ability to physiologically optimise the patient was severely limited by his underlying pathology. Furthermore, the concomitant acute kidney injury and hyperdynamic cardiac function may have progressively worsened the pulmonary oedema, exacerbating the interplay between these physiological systems. While a direct relationship between hypercalcaemia and pulmonary oedema is not well established, it is felt this case demonstrates potential causation. Additionally, given the marked improvement in clinical state following removal of the source of hypercalcaemia, we believe this further emphasises the multi-system effects associated with high serum calcium levels. Further case reports and studies are required to analyse the links between calcium and multi-organ failure in more detail.
Footnotes
Acknowledgements
Thanks to elective medical student M. Pielas for his interpretation skills during this case, and Dr. M. McCooe for his support.
Authors’ contributions
All authors contributed to the literature search and writing of the case report.
Availability of data and material
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
Consent for publication
Written consent was obtained from the patient.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval and consent to participate
Written consent was obtained from the patient.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.