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J Clin Pathol. 2007 April; 60(4): 436–437.
PMCID: PMC2001100

Pseudo‐pseudohypercalcaemia, apparent primary hyperparathyroidism and Waldenström's macroglobulinaemia

Abstract

An apparent primary hyperparathyroidism was reported due to pseudo‐pseudohypercalcaemia in a 74–year‐old man with Waldenström's macroglobulinaemia. It is important to recognise artificially elevated serum calcium levels so as to avoid erroneous diagnosis, unnecessary investigations and potentially inappropriate treatment.

Waldenström's macroglobulinaemia is a malignant disorder of B lymphocytes characterised by high serum concentrations of monoclonal IgM, a lymphoplasmacytic infiltrate of the bone marrow and an elevated serum viscosity.1,2 Hypercalcaemia is unusual in Waldenström's macroglobulinaemia2 but a characteristic feature of primary hyperparathyroidism. Although Waldenström's macroglobulinaemia is uncommon, primary hyperparathyroidism is relatively common. It is, therefore, possible that the two conditions may coexist. We describe a case of apparent primary hyperparathyroidism due to pseudo‐pseudohypercalcaemia in association with Waldenström's macroglobulinaemia.

Case report

A 74‐year‐old man was diagnosed with Waldenström's macroglobulinaemia when he presented in May 2002 with lethargy, weight loss and nasal bleeds, and an IgM κ paraprotein of 31.5 g/l (IgM reference range: 0.5–2 g/l). He received chemotherapy courses and in February 2003 was referred to the urologists with prostatism. His rectal examination was normal; however, his serum prostate‐specific antigen (PSA) was raised (17 μg/l; reference range 0.1–6.5 μg/l; age [gt-or-equal, slanted]70 years). A four‐quadrant prostatic biopsy followed, but did not show malignant infiltration of the prostate. At an oncology review in April 2003, it was noticed that he had asymptomatic hypercalcaemia (serum adjusted calcium level 2.86 mmol/l; reference range 2.17–2.66 mmol/l; Arsenazo III dye binding method). A persistently elevated serum PSA of 52.2 μg/l measured in May 2003 had instigated a second four‐quadrant prostatic biopsy, which was inconclusive of a diagnosis of prostatic carcinoma. Serum calcium levels remained elevated at 2.89 mmol/l. The possibility of hypercalcaemia due to metastatic bone disease, although uncommon in patients with prostate cancer despite the high frequency of skeletal metastases, prompted an isotope bone scan; however, it did not show any metastatic lesions. The diagnosis of primary hyperparathyroidism was then considered on the basis of the presence of a consistently elevated serum adjusted calcium level of 3.03 mmol/l with inappropriately non‐suppressed two serum parathyroid hormone results (4 and 4.4 pmol/l; reference range 1.6–6.9 pmol/l, DPC immulite) and a normal serum creatinine level of 94 μmol/l. Subsequently, an ultrasound of the neck was performed, which suggested the presence of a parathyroid adenoma in the posteroinferior part of the left thyroid lobe. However, in July 2003, on metabolic review, the presence of a normal serum ionised calcium level of 1.10 mmol/l (reference range 1.11–1.3 mmol/l measured on a Radiometer ABL700) and a normal fasting urine calcium excretion of 0.012 mmol/l GF (reference range CaE <0.045 mmol/l GF) has excluded genuine hypercalcaemia despite the repeatedly elevated serum adjusted calcium level of 3.1 mmol/l.

Take‐home messages

  • It is important to investigate elevated serum calcium levels in association with paraproteinaemias, especially in patients with Waldenström's macroglobulinaemia where genuine hypercalcaemia is rare.
  • True hypercalcaemia in these patients could be confirmed by measurement of plasma ionised calcium with or without urinary calcium excretion.
  • Increased paraprotein concentrations in these patients interfere with the calcium Arsenazo ΙΙΙ reagent, and elevated serum calcium level could be remeasured using the o‐cresolphthalein complexone method.
  • Confirmation of falsely elevated serum calcium levels will prevent erroneous diagnosis, unnecessary investigations and potentially inappropriate treatment.

The diagnosis of pseudohypercalcaemia was made and was postulated to be due to an abnormal binding of calcium molecules to the IgM paraprotein.3 This was, however, excluded when gel filtration chromatography showed a similar pattern between the patient's sample and that of a normal control. Both samples showed two peaks of calcium: the first peak associated with albumin and the second peak represented the complexed calcium; however, none was associated with the IgM paraprotein, thus excluding calcium–paraprotein binding as a cause of the falsely elevated serum calcium levels. Additional investigation with measurement of serum calcium level on the same patient's sample (serum adjusted calcium level of 3.1 mmol/l) with the o‐cresolphthalein complexone (CPC) method gave a calcium level of 2.19 mmol/l (reference range 2.1–2.55 mmol/l), and with atomic absorption spectrophotometry gave a calcium level of 2.4 mmol/l (reference range 2.2–2.6 mmol/l). All these findings led to the conclusion of interference of the IgM paraprotein with the Arsenazo III dye binding calcium method.4

In November 2003, histological examination of repeat four‐quadrant prostatic biopsies in the presence of a PSA of 79 μg/l (reference range 0.1–6.5 μg/l; age [gt-or-equal, slanted]70 years) had confirmed the diagnosis of an adenocarcinoma for which he is currently receiving treatment.

Serum calcium level in January 2004, measured by a CPC method, was 2.21 mmol/l (reference range 2.1–2.55 mmol/l).

Discussion

The presence of pseudo‐pseudohypercalcaemia in association with Waldenström's macroglobulinaemia had resulted in an erroneous provisional diagnosis of primary hyperparathyroidism. In patients with Waldenström's macroglobulinaemia, genuine hypercalcaemia is rare1,2 and pseudohypercalcaemia is even rarer.3,4 Indeed, there were only two case reports of pseudohypercalcaemia in Waldenström's macroglobulinaemia due to either calcium binding to the IgM paraprotein3 or paraprotein interference in the calcium Arsenazo ΙΙΙ method.4 The findings for this patient are consistent with the notion of IgM paraprotein interference with the calcium Arsenazo ΙΙΙ method and the consequent pseudo‐pseudohypercalcaemia.4 The mechanism of the interference is likely to be increased turbidity produced by paraprotein interaction with the acidic medium of the calcium Arsenazo ΙΙΙ reagent and not with the alkaline CPC method.4

It is possible that if the pseudo‐pseudohypercalcaemia had not been recognised, this patient would have had an unnecessary neck exploration, since persistent hypercalcaemia (as in this case) is an indication for parathyroid surgery irrespective of symptoms or complications of primary hyperparathyroidism.5

Conclusion

We report a case of apparent primary hyperparathyroidism due to pseudo‐pseudohypercalcaemia in association with Waldenström's macroglobulinaemia.

We conclude that it is important to identify patients with falsely elevated serum calcium levels in patients with paraproteinaemias to prevent unnecessary investigations, erroneous diagnosis and potentially inappropriate treatment.

Since pseudo‐pseudohypercalcaemia in association with Waldenström's macroglobulinaemia may be multifactorial in origin, we suggest that apparent hypercalcaemia in these patients should be confirmed by measurement of plasma ionised calcium with or without urinary calcium excretion.

Abbreviations

CPC - cresolphthalein complexone

PSA - prostate‐specific antigen

Footnotes

Competing interests: None declared.

Informed consent was obtained from the patient described in this report.

References

1. Dimopoulos M A, Panayiotidis P, Kouropoulos L A. et al Waldenstrom's macroglobulinaemia: clinical features, complications and management. J Clin Oncol 2000. 18214–226.226 [PubMed]
2. Dimopoulos M A, Galani E, Matsouka C. Waldenstrom's macroglobulinaemia. Hematol Oncol Clin North Am 1999. 131351–1366.1366 [PubMed]
3. Side L, Fahie‐Wilson M N, Mills M J. Hypercalcaemia due to calcium binding IgM paraprotein in Waldenstrom's macroglobulinaemia. J Clin Pathol 1995. 48961–962.962 [PMC free article] [PubMed]
4. Rhys J, Oleesky D, Issa B. et al Pseudohypercalcaemia in two patients with IgM paraproteinaemia. Ann Clin Biochem 1997. 34694–696.696 [PubMed]
5. Bilezikian J P, Potts J T, Jr, Fuleihan G E. et al Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab 2002. 875353–5361.5361 [PubMed]

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