Abstract
This report describes the presentation and clinical course of a 40-year-old woman who had an emergency admission for eclampsia. During routine investigations, she was found to have profound hypercalcaemia, the cause of which was identified as milk-alkali syndrome, caused by self-medication with antacid tablets for dyspepsia. Treatment with aggressive rehydration, bisphosphonates and discontinuation of antacid tablets restored normocalcaemia. The patient made a full recovery with no long-term side-effects. Her male infant was safely delivered with no deleterious effects of exposure to high calcium concentrations in utero.
Case
A 40-year-old woman presented to the Accident and Emergency Department with a loss of consciousness, fits and hypertension (Glasgow Coma Scale [GCS] 15, blood pressure 169/90 mmHg, pulse 90 beats/minute). She was a known manic-depressive who was prescribed lithium carbonate and the antidepressant venlafaxine, and had a history of domestic abuse, illicit drug use and pre-eclampsia. Prior to admission, she had complained of malaise and fatigue. On examination, she was found to be 38 weeks pregnant (Gravida 8, Para 5). The pregnancy had been concealed and she had therefore not received any antenatal care.
Differential diagnoses on admission were overdose, eclampsia and encephalitis. Blood taken for routine investigations showed her to be markedly hypercalcaemic (corrected calcium 4.71 mmol/L) with mild renal impairment (Table 1). Despite this, in light of previous history and clinical presentation, a diagnosis of eclampsia was made. The patient was given a bolus of 4 g MgSO4 over 15 minutes followed by an infusion of 1 g/hour and transferred to theatre for an emergency caesarean section.
Routine investigations performed during the course of admission
CRP, C-reactive protein; WCC, white cell count
*Day of admission
A live male infant was delivered (2.335 kg, apgar 3 and 8 at 1 and 10 minutes, respectively) and transferred to the neonatal intensive care unit (NICU).
Following surgery, the patient was transferred to the ICU where she was sedated and ventilated. A rehydration regimen with normal saline was commenced and di-sodium pamidronate (15 mg twice daily) to treat the hypercalcaemia, together with ramipril to stabilize her blood pressure. A computed tomography scan of her head to rule out a pathological cause for the fits was normal.
The patient remained on ICU for 24 hours prior to transfer to the high-dependency unit and subsequently the obstetric ward. During this time, her calcium concentrations fell, her blood pressure normalized, bisphosphonate and fluid treatment were stopped on days 4 and 5, respectively. Owing to the onset of depression, lithium therapy was recommenced on day 5.
Biochemical investigations to elucidate the cause of her hypercalcaemia were unhelpful, demonstrating normal thyroid, adrenal and parathyroid function, normal tumour markers and normal serum and urine electrophoresis (Table 2).
Investigations performed in the assessment of hypercalcaemia
PTH, parathyroid hormone; TSH, thyroid-stimulating hormone; AFP, alphafetoprotein; s-ACE, serum angiotensin converting enzyme
A review by the endocrine team revealed that during pregnancy she had stopped lithium therapy but had continued to take venlafaxine. During pregnancy, she had suffered with thirst and had developed nocturia 3–4 times per night. She was a smoker (20–60 per day) and had frequent bouts of bronchitis. She denied alcohol and illicit drug use. There was no family history of calcium, parathyroid or other endocrine problems. Upon further questioning, the patient revealed that she regularly took an unknown multivitamin preparation and because of dyspepsia during pregnancy had self-medicated with antacids (approximately 24 tablets per day) and four pints of milk per day. This resulted in a calcium intake of approximately 11 g/day (normal calcium intake 700–900 mg/day).
In the absence of any other identifiable cause for the hypercalcaemia and its resolution upon withdrawal of excess calcium intake, a retrospective diagnosis of milk-alkali syndrome (MAS) was made.
The patient made a full recovery from the eclamptic episode and two weeks after presentation remained normocalcaemic (corrected calcium 2.37 mmol/L; reference range 2.2–2.6 mmol/L). The infant made good progress on NICU and was discharged home with no apparent ill effects caused by the exposure to high concentrations of calcium in utero.
Discussion
MAS is a rare, serious and potentially life-threatening cause of hypercalcaemia. Typically, it is thought of as a historical disease occurring as a complication of the treatment of peptic ulcer disease using the Sippy regimen: an antacid regimen aimed at neutralizing gastric acid and to promote healing of peptic ulcers. 1,2 The advent of histamine-2 (H2) receptor blockers for the treatment of peptic ulcers in the early 1980’s has significantly reduced the incidence of the condition; however, a small number of cases continue to be reported, with the majority linked to over-the-counter antacid preparations. 3,4
MAS is characterized by the metabolic triad of hypercalcaemia, renal impairment and metabolic alkalosis together with a history of excess calcium and absorbable alkali intake. The symptoms associated with the condition are consistent with those observed in hypercalcaemic states (e.g. nausea, vomiting, urinary frequency and electrocardiography changes). If left unrecognized, it can lead to metastatic calcification, renal failure and death.
The mechanisms through which the metabolic sequelae develop have been characterized 5 and create a vicious circle leading to perpetuation of symptoms. Ingested calcium is primarily absorbed in the duodenum, under the regulation of 1,25 OH2 vitamin D, where it reacts with the intestinal acid to produce ionized calcium. 6 This may be neutralized by sodium bicarbonate to produce a CaCO3 precipitate, which further reacts with inorganic phosphate to form a precipitate or be absorbed in the duodenum leading to the development of hypercalcaemia. The hypercalcaemia causes a renal concentrating defect because of resistance to the action of arginine vasopression on the collecting duct: a form of nephrogenic diabetes insipidus. The resultant dehydration and volume depletion may worsen the hypercalcaemia and the concomitant vomiting associated with hypercalcaemia worsens the volume depletion. Volume depletion leads to a reduction in the glomerular filtration rate (GFR), while hypercalcaemia causes arteriolar vasoconstriction in the kidney leading to a reduction in tubular sodium re-absorption, acute tubular necrosis, nephrocalcinosis and tubulointerstitial fibrosis. This can cause renal dysfunction through decreased GFR or direct tubular damage.
The development of metabolic alkalosis is not due solely to the ingestion of alkaline substances, such as the calcium carbonate found in antacid tablets, as even in large amounts the quantity of absorbable alkali contained within them is not sufficient to cause a metabolic alkalosis. 7 Instead, the alkalosis develops because of the hypercalcaemia and the associated suppressed parathyroid hormone (PTH) that stimulate the Na+/H+ exchanger to secrete hydrogen ions and therefore increase the renal re-absorption of bicarbonate. Alkalosis causes increased calcium resorption in the distal collecting system of the kidney, compounding the degree of hypercalcaemia.
Treatment of MAS is reliant on discontinuation of the source of excess calcium and absorbable alkali, coupled with volume repletion and if necessary, calciuric therapy. Volume repletion is aggressive and aimed at breaking the perpetuating cycle of metabolic abnormalities triggered by the hypercalcaemia. During volume repletion, it is essential that electrolyte concentrations are monitored and depleted analytes replaced. Fluid balance must also be assessed and volume overload treated with diuretics. If necessary, calcitonin therapy can be used to promote calciuria. In patients whose calcium concentrations fail to fall following rehydration and pharmacological interventions, haemodialysis using a calcium-free dialysate may be useful.
The risk of developing MAS during pregnancy is increased due to a state of increased calcium absorption, mediated by human placental lactogen, 1,25 di-hydroxy vitamin D and prolactin. 8 This, together with the potential for volume depletion caused by hyperemesis, may predispose pregnant women to develop MAS. 9 In addition to the deleterious effects on maternal health caused by MAS, the exposure of the fetus to hypercalcaemia in utero can cause significant morbidity and mortality. 10 Despite this, only a small number of cases are reported in the literature. 4,11,12
The patient described in this report was a multiparous woman who presented with seizures associated with eclampsia. Routine biochemical investigations demonstrated significant hypercalcaemia and a metabolic alkalosis, which was subsequently attributed to MAS caused by the ingestion of a large number of antacid tablets coupled with a high milk intake, resulting in a total calcium intake in excess of 11 g per day. Unexpectedly, serum PTH measured on day 2 was low-normal. The reason for the lack of suppression of PTH in the presence of hypercalcaemia is unclear although it may be in part related to the 24 hours of aggressive rehydration and pamidronate therapy that had been administered prior to sample collection. During this 24-hour period, the serum calcium fell from 4.71 to 3.91 mmol/L and the rate and the magnitude of this change may have had an effect on serum PTH concentrations. However, there is no evidence in the literature to support this theory. Following treatment, the hypercalcaemia resolved and three months after discharge the patient remained normocalcaemic.