Forgotten but not gone: calcium‐alkali syndrome

Calcium‐alkali syndrome (CAS) is characterised by hypercalcaemia, metabolic alkalosis, and renal injury. CAS has been a long‐standing concern but has fallen off the radar in recent times. However, supplementation of calcium and vitamin D for osteoporosis, and use of calcium based antacids for reflux has led to its resurgence as one of the leading causes for hypercalcaemia‐induced hospitalisations.


INTRODUCTION
Milk-alkali syndrome is now more commonly termed calcium-alkali syndrome (CAS) due to its re-emergence and association with calcium supplementation for osteoporosis.][3] CAS is characterised by the triad of hypercalcaemia, renal failure, and metabolic alkalosis caused by the coingestion of calcium and absorbable alkali. 4Elderly, especially female, patients have a greater susceptibility secondary to increased prevalence and treatment of osteoporosis, which often includes calcium supplementation, age-related decline in kidney function, and the co-prescribing of medicines that reduce the glomerular filtration rate (GFR). 5pproximately 11% of the Australian population suffers from chronic gastroesophageal reflux disease, with greater prevalence in elderly people. 6Calcium carbonate-containing antacids are extremely popular over-the-counter (OTC) medicines due to their high potency, as well as the rapid and long duration of action. 7Quick-Eze tablets are one of the most commonly used OTC calcium-containing antacids across Australia, with a labelled recommended dose of up to 9 g per day. 8However, CAS has been reported at minimal daily doses of 1-1.5 g in patients with risk factors such as altered renal function. 4We report a case of CAS in an 84-year-old woman who developed severe hypercalcemia following long-term consumption of 4.6-6 g of Quick-Eze tablets, with clinical improvement following discontinuation and symptomatic management.

CASE REPORT Patient Consent Statement
The Western Sydney Local Health District Human Research Ethics Committee does not require ethics approval for case reports.The patient's free, prior, and informed consent to publish this case report was obtained and documented.
An 84-year-old woman presented to the emergency department (ED) with gradual onset of severe and constant substernal chest pain, a tingling sensation in her left hand, unsteady gait, and two episodes of vomiting over the past 4 days.Her medical history included chronic obstructive pulmonary disease, hypothyroidism, type 2 diabetes, hypertension, dyslipidaemia, osteoarthritis, pulmonary embolism, cholecystectomy, hysterectomy, and pancreatitis.
Four months later, the patient re-presented to the ED of another hospital during a COVID-19 lockdown with a 3-day history of nausea, abdominal pain, drowsiness, and confusion.On examination, she was clinically volume depleted with generalised bony and abdominal tenderness.Cardiac and respiratory examinations were unremarkable.Admission investigations showed SCr 255 lmol/L, eGFR 14 mL/min/1.73m 2 , bicarbonate 37 mmol/L, and a corrected calcium level of 4.62 mmol/ L (RR 2.10-2.6 mmol/L).A presumptive diagnosis of severe symptomatic hypercalcaemia and AKI was made, and she was treated with IV hydration, frusemide 40 mg twice daily, and 30 mg pamidronate.The patient's kidney function recovered partially and she was discharged with SCr and eGFR of 159 lmol/L and 26 mL/min/1.73m 2 , respectively, and a corrected calcium of 2.33 mmol/L.
On questioning, the patient admitted to frequently consuming 6-8 Quick-Eze tablets/day (4.5-6 g calcium carbonate) for the severe reflux symptoms she was suffering prior to the first admission and once her discharge esomeprazole tablets were finished.On followup after 2 weeks, her kidney function improved significantly (SCr 85 lmol/L, eGFR 54 mL/min/1.73m 2 ).The clinical picture was deemed to be due to CAS resulting from excessive consumption of OTC Quick-Eze tablets.

DISCUSSION
CAS, previously known as milk-alkali syndrome (MAS), consists of the triad of hypercalcaemia, metabolic alkalosis, and renal impairment. 4MAS was first described in reference to patients treated for peptic ulcer disease (PUD) with milk and sodium bicarbonate therapy. 4Whilst MAS was responsible for <1% of hypercalcaemia cases post the advent of histamine-2 receptor antagonists and proton pump inhibitors (PPIs) for PUD, more recent cases of hypercalcemia have largely been secondary to the use of calcium carbonate for osteoporosis and hyperphosphatemia with chronic kidney disease. 4ue to the changing aetiology and varied presentations, CAS can be easily missed, as seen in our case during the first admission where, surprisingly, the patient's calcium levels were not measured.It is unclear why only a minority of exposed patients develop the syndrome. 9The factors that would have increased the susceptibility in our patient included the 2000 IU vitamin D capsules she was consuming (for osteoporosis management) and Gaviscon dual action 20 mL three times a day (calcium carbonate 32.5 mg/mL, sodium bicarbonate 21.3 mg/mL, sodium alginate 50 mg/mL).She was also unable to secure scripts for esomeprazole prescribed during the first admission due to a COVID-19 lockdown, where she was reviewed via telehealth, and her GP's reluctance to continue prescribing esomeprazole.
This case highlights the need for patients with reflux symptoms to be educated on the risks associated with the use of OTC Quick-Eze tablets.The packaging instructions recommend taking Quick-Eze for temporary relief of reflux symptoms only and recommended a maximum daily dosage of 12 tablets for adults. 9Appropriate warning labels are warranted to prevent further cases of this type, as the amount of calcium carbonate required to be ingested per day to cause CAS varies widely, with cases reported at doses <4 g a day. 10 In addition, the benefits and appropriateness of PPI therapy need to be considered carefully alongside the potential long-term risks, despite recent studies highlighting the consequences of long-term PPI use in older people and the need for deprescribing. 11Finally, the importance of accurate and timely medication history interviews cannot be overemphasised as they are essential in identifying possible aetiologies and preventing adverse complications, in addition to reducing investigation-related financial and psychological burdens.Given their proficiency in medication history taking, pharmacists play a key role in preventing such complications.Vital medicine-related information was missed during the patient's initial visit to hospital, which led to worsening of her condition and a subsequent visit to the ED.
This case serves as a reminder for clinicians that CAS may be forgotten, but not gone, and the importance of good history-taking, including information about prescription medicines and the use of OTC drugs during evaluation.

ACKNOWLEDGEMENT
Open access publishing facilitated by The University of Sydney, as part of the Wiley -The University of Sydney agreement via the Council of Australian University Librarians.