To the Editor: The interesting article by Gordon et al1 warrants further discussion with regard to the hypophosphataemia, “inappropriately” high level of serum 25‑hydroxyvitamin D, biochemical diagnosis of pancreatitis and management of hypercalcaemia.

Fibroblast growth factor-23 (FGF-23) is a recently described 254‑amino-acid peptide that has been shown to have significant phosphaturic effect. It probably plays a major role in phosphate metabolism and homeostasis by rising after an oral phosphate load and falling after dietary phosphate restriction. In the patient discussed by Gordon et al, elevated FGF-23 level may, hypothetically, have been a major contributing factor to the low serum phosphate level. Although the understanding of this factor is still in its infancy, measuring the serum level of FGF-23 in the patient might have shed more light on the role of FGF-23 in phosphate homeostasis. However, FGF-23 levels do not correlate directly with serum phosphate levels, suggesting that FGF-23 exercises control via renal tubular cells, regulation of calcitriol levels or intestinal phosphate absorption. FGF-23 levels are also markedly elevated in chronic renal failure, partly in response to the chronic hyperphosphataemia and partly because of reduced renal clearance.2 Its action is independent of the traditional and better understood regulators of phosphate level, including parathyroid hormone and parathyroid hormone-related protein.

The triad of high vitamin D level, hypercalcaemia and hypophosphataemia points strongly to a diagnosis of vitamin D intoxication, despite a patient history to the contrary. An alternative explanation is an inaccurate vitamin D assay from the supporting laboratory. This issue, which has been highlighted recently, has therapeutic relevance in monitoring vitamin D replacement therapy.3

In supporting the diagnosis of pancreatitis, serum lipase level remains the best biochemical test and is more specific than amylase level.4 The practice of dual amylase and lipase ordering in the investigation of such conditions is excessive, confusing and costly to the community and should be discouraged.

The indication for bisphosphonate treatment in milk-alkali syndrome remains unclear and contradicts the underlying pathogenesis, which is believed to be that of excessive calcium ingestion. In the patient in question, excessive calcium ingestion overwhelmed the calcium homeostatic mechanism, resulting in severe hypercalcaemia. In such a milieu, osteoclasts would be heavily suppressed and inhibited, and thus the use of a bisphosphonate, whose major action is also by osteoclastic suppression, would be of little value other than in precipitating hypocalcaemia.5 Thus, expectant management as outlined by the authors would be sufficient to achieve normocalcaemia. As bisphosphonates are not without adverse effects,6 they should only be used after a clear diagnosis of hypercalcaemia has been made.

To the Editor: I read with interest the Lessons from Practice article on milk-alkali syndrome during pregnancy.1 I would like to offer the following comments.

The patient’s alkalosis was in fact more impressive than presented, as the authors used the reference range for serum bicarbonate in non-pregnant patients. During pregnancy, serum bicarbonate levels typically fall by about 4 mmol/L to compensate for the respiratory alkalosis caused by elevated progesterone levels stimulating respiratory drive.

Given the patient’s life-threatening calcium level on presentation, I am interested to know whether calcitonin treatment or even dialysis was considered while waiting for the pamidronate to take effect.

An important aspect that the authors did not discuss in relation to this case is the reassuring data on the safety of both proton-pump inhibitors and H2-receptor antagonists in pregnancy. While there is more experience with the latter, two recent studies found no evidence of teratogenicity in almost 900 cases of exposure to proton-pump inhibitors in the first trimester.2,3 Clinicians should feel comfortable about prescribing these medications in pregnancy.

After reporting a similar case,4 I wrote to Walco, the manufacturers of Quick-Eze, who subsequently changed their product labelling to include a warning about the number of tablets that could be safely taken each day. Disappointingly, they did not include a warning about ingestion during pregnancy, as I suggested.

In reply: Our case appears to be consistent with typical milk-alkali syndrome. While measuring fibroblast growth factor-23 (FGF-23) level might have been of hypothetical interest, it is unlikely that it would have influenced management. Vitamin D intoxication was considered once the 25-hydroxyvitamin D results became available, and we closely questioned our patient in relation to this possibility. She was insistent that she had not taken any vitamin D supplements. It is possible either that the patient did not wish to admit to taking vitamin D or that the assay was misleading, as suggested by Tran. We agree that bisphosphonate therapy should not be advocated when the diagnosis of milk-alkali syndrome is clear. In this case, however, the patient was drowsy and very ill; the full history relating to antacid ingestion was not obtained until after the bisphosphonate therapy had been given.

With regard to Morton’s comments, the hypercalcaemia settled promptly, so fortunately calcitonin treatment and other measures did not need to be considered. Drug safety in pregnancy is a difficult issue, as the effects of fetal or neonatal damage may carry lifelong implications, and even relatively rare associations need to be considered with care. In addition, many pregnant women are uncomfortable about taking prescription medications during pregnancy, even though their doctors may have a more relaxed view. Currently, over-the-counter antacids are classed as category A drugs for pregnancy, whereas H2-receptor antagonists and proton-pump inhibitors are category B1 and B3, respectively. Cimetidine has been associated rarely with neonatal hepatic abnormalities,1 and it is still too early to state with confidence that proton-pump inhibitors are “safe”, despite promising initial analyses. Ironically, the potential dangers of over-the-counter calcium-containing antacids, as demonstrated in this case report and others, are not currently adequately acknowledged. We have written to the manufacturers of Rennie tablets requesting a package label warning advising consumers not to exceed six tablets a day.