Poster Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

A Calcium Conundrum (#102)

Jade Eccles-Smith 1 , Emma Duncan 1 2
  1. Department of Endocrinology, The Royal Brisbane and Women's Hospital, Herston, QLD, Australia
  2. Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia

We report a challenging and complex case of hypercalcaemia with both diagnostic and management dilemmas in a women now aged 52 years.

She has a complex psychosocial background. An eating disorder was diagnosed in early adulthood, but she has not attended psychological assessment or support for many years. Her children were removed for foster care; she now has contact with some but not others. She is not currently partnered. Her GP manages her anxiety and depression currently with dothiepin and quetiapine. Other history includes migraines (on pizotifen) and a hysterectomy for cervical cancer.

 

In 2015 she underwent an elective retrieval and replacement of bilateral breast implants (date of first implants unknown). Postoperatively, she developed an acute kidney injury with oliguric renal failure. Investigations demonstrated a bland urine sediment with no malignant cells, proteinuria (40g/mol creat), a normal kidney, ureter and bladder ultrasound, negative vasculitis screen, and normal calcium and phosphate. Renal biopsy was consistent with acute tubular necrosis, presumed due to cephalosporins. She required haemodialysis for three months. During this time, her nadir calcium was 2.0mmol/L and she was prescribed Caltrate. She was left with a chronic kidney injury (creatinine 120umol/L with eGFR 40-70mL/min but calculated creatinine clearance using Cockcroft-Gault formula 38mL/min).

 

Twelve months later she presented with nausea and vomiting. She had hypercalcaemia (corrected calcium 3.32mmol/L) with a deterioration in renal function (creatinine 303umol/L). Parathormone (PTH) at this time was 1.8pmol/L. She was treated acutely with intravenous rehydration and calcium supplement cessation, with resolution of hypercalcaemia and return to baseline renal function.

 

Subsequently, she started to present almost fortnightly with similar levels of hypercalcaemia and deteriorating renal function. Her highest corrected calcium was 3.69mmol/L, with phosphate 1.88mmol/L, magnesium 0.09mmol/L and creatinine 292umol/L. Apart from a PTH of 0.8 pmol/L early on, all other PTH readings have been inappropriately normal or, on rare occasion, frankly elevated (maximum 12pmol/L). Of note, she frequently presents with concomitant hypokalaemia and normal or frankly elevated bicarbonate.

 

She has been extensively investigated by the various teams involved in her care:

99Sestamibi-CT scan February 2016 demonstrated possible faint accumulation at lower pole of right thyroid; however, SPECT-CT did not localise this focus to a specific anatomical abnormality. A neck ultrasound did not identify a parathyroid adenoma. Repeat 99Sestamibi-CT (March 2018) did not add to previous findings.

  • 25(OH)Vitamin D was 46nmol/L
  • 1,25(OH)2Vitamin D was 41pmol/L (48-190); concomitantly, corrected calcium was 3.41mmol/L (subsequently repeated at 22pmol/L).
  • Serum ACE was initially 62U/L (20-70); when repeated this had increased to 96U/L  (ACE mass 222ug/L (37-211). ANA, dsDNA and ENA all unremarkable.
  • FDG-PET demonstrated physiologic uptake, without evidence of granulomatous disease.
  • MRI breasts demonstrated intact implants without leakage.
  • HDP-labelled bone scintigraphy was normal.
  • Serum electrophoresis, serum and urinary light chains, and b2-microglobulin were normal.
  • CT chest/abdomen/pelvis was unremarkable.
  • PTH-related peptide was negative (<2.0pmol/L)
  • Urinary calcium has ranged between 1 .4 mmol/24hour (NR 2.5-7.5) (1.339L) and 5.1mmol/24hours (1.715L ).
  • Multiple negative diuretic screens.
  • Calcium-sensing receptor screening was unremarkable.
  • 4D-CT was not undertaken due to concerns that contrast might push her into permanent dialysis.

Assay -interference with PTH measurement was discussed with the chemical pathologists but thought unlikely.

 

During a supervised admission her observed behaviours included ingesting large volumes of milk, as well as concerns for purging behaviours. Notably, she repeatedly denies drinking milk at home when presenting with hypercalcaemia.

 

Currently the working diagnosis is milk-alkali syndrome, possibly also with a contribution from primary [or tertiary] hyperparathyroidism.

 

Management has proven almost impossible:

  • Multiple attempts have been made for her to see the Eating Disorders Unit, without success.
  • The renal unit initially trialled Prednisolone at dose 1mg/kg, without significant improvement.
  • Pamidronate 60mg was trialled in late 2017 with no deterioration of renal dysfunction and some mild control of hypercalcaemia for a few months, in that she did not attend hospital for three months. This also concorded with a discussion with her about milk-drinking behaviours. She has received three pamidronate doses to date.
  • A trial of cinacalcet (initially 30mg, uptitrated to 60mg) made little improvement. Poor adherence was considered likely and she was admitted for observation, but self-discharged.

 

Her weight over the past three years has varied between 37.4kg and 40.7kg (BMI 15-16.2 kg/m2). She is secretive about her eating behaviours. Her recently-re-united daughter confirmed mis-reporting of oral intake; subsequently the patient become estranged from this daughter and withdrew consent for us to contact her.

 

Her creatinine is worsening over time. Current calculated creatinine clearance is 20mL/min. She is not attending renal outpatients.

 

Milk-alkali syndrome (MAS) is the triad of hypercalcaemia, metabolic alkalosis and acute kidney injury following ingestion of large volumes of calcium and alkali. It was previously common with the Sippy protocol for peptic ulcer disease but became rare after introduction of proton pump inhibitors and H2-blockers. More recently there has been resurgence, due to widespread use of calcium carbonate (e.g. Caltrate, Quickeze). MAS is now the third most common cause of hypercalcaemia and accounts for 12% of presentations.1-3 The amount of calcium required to cause MAS varies but is thought in the order of 10-20g of elemental calcium per day, equal to many complete rolls of antacid tablets or 10-20L of milk.4

Treatment consists of cessation of ingestion and rehydration.3

PTH suppression is usually but not always observed in MAS.4 Some authors argue that abrupt improvement in hypercalcaemia with treatment causes rebound PTH rise; this argument implies, though, that PTH would still be appropriately suppressed before treatment.2,3 CKD may also predispose to MAS. Patients with CKD often have unsuppressed PTH despite significant hypercalcaemia, due to tertiary hyperparathyroidism; this usually requires years of CKD to develop, however. Whether the occasional non-suppression of PTH in MAS is related to concomitant CKD per se, or to other mechanism(s), is unknown.4

Clinical Questions

  1. Is the diagnosis secure? Is there more than one process going on?
  2. What strategies improve hypercalcemia in a woman with chronic malnutrition due to disordered eating and possible MAS?
  3. What other therapies might help her hypercalcaemia, renal function and prevent admissions?
  4. Is there any role for neck exploration?
  1. Cope CL. Base changes in the alkalosis produced by the treatment of gastric ulcer with alkalis. Clin Sci. 1936;2:287.
  2. Beall D, Scofield H. Milk-Alkali Syndrome Associated with Calcium Carbonate Consumption: Report of 7 Patients with Parathyroid Hormone Levels and an Estimate of Prevalence Among Patients Hospitalized with Hypercalcemia. Medicine. 1995;74(2):89-96.
  3. Picolos M, Lavis V, Orlander P. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. Clinical Endocrinology. 2005;63(5):566-576.
  4. Medarov B. Milk-Alkali Syndrome. Mayo Clinic Proceedings. 2009;84(3):261-267.