Pseudo-pseudohypercalcaemia, apparent primary hyperparathyroidism and Waldenström's macroglobulinaemia.

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.

Hypoglycemia due to an insulin binding antibody in a patient with an IgA-kappa myeloma.

CONTEXT: Autoantibodies to insulin have been described to cause spontaneous hypoglycemia in nondiabetic subjects. There have been occasional reports of spontaneous hypoglycemia due to monoclonal anti-insulin antibodies. We present the first report of a patient with an IgA-kappa myeloma in whom frequent hypoglycemia resulted from the ability of the monoclonal IgA-kappa to bind insulin. OBJECTIVES: The aim of this study was to describe the occurrence of profound hypoglycemia in a patient with IgA-kappa myeloma, characterize biochemically the nature of the IgA:insulin complex present, and place this case in the context of the published literature on hypoglycemia resulting from autoantibodies to insulin. DESIGN: A case study was performed. PATIENTS: A single case of profound hypoglycemia associated with IgA-kappa myeloma was studied. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: A case study was performed. RESULTS: Polyethylene glycol precipitation and gel filtration chromatography were used to demonstrate high-molecular weight insulin immunoreactivity in the patient's plasma. This was characterized as an insulin binding IgA-kappa paraprotein present at 4200 mg/dl (42 g/liter) with a relatively high insulin dissociation constant of 0.32 microm/liter using radiolabelled insulin binding studies. CONCLUSIONS: We present the first case of hypoglycemia due to IgA binding insulin antibodies in a patient with an IgA-kappa paraprotein myeloma. The hypoglycemia was associated with high-plasma insulin levels and relatively low C-peptide levels. A plausible mechanism for the hypoglycemia is the delayed clearance of insulin. This case broadens the spectrum of monoclonal gammopathies that have been associated with anti-insulin reactivity and spontaneous hypoglycemia.

Macroprolactin; high molecular mass forms of circulating prolactin.

Two high molecular mass forms of prolactin (PRL) in serum have been identified by gel filtration chromatography (GFC): macroprolactin (big-big PRL, > 100 kDa) and big PRL (40-60 kDa). Macroprolactin has a variable composition and structure, but is most frequently a complex of PRL and IgG, with a molecular mass of 150-170 kDa. It is formed in the circulation following pituitary secretion of monomeric PRL but has a longer half-life, and the PRL in the complex remains reactive to a variable extent in immunoassays. In the majority of subjects little or no macroprolactin can be detected in serum, but in some individuals it may be the predominant immunoreactive component of circulating PRL and the cause of apparent hyperprolactinaemia. Owing to its high molecular mass, macroprolactin appears to be confined to the intravascular compartment and much evidence indicates that it has minimal bioactivity in vivo and is not of pathological significance. Nevertheless, hyperprolactinaemia due to macroprolactin can lead to diagnostic confusion and unnecessary further investigation and treatment if it is not recognized as such. Macroprolactin is a common cause of apparent hyperprolactinaemia with some assays and it is essential that laboratories introduce screening programmes to examine samples with elevated total immunoreactive PRL for the presence of macroprolactin and determine the monomeric PRL component which is known to be bioactive in vivo. A number of screening tests have been described; that based on the precipitation of macroprolactin with polyethylene glycol has been the most widely validated and applied. The reference technique of GFC should be available for confirmation and further investigation of samples, giving equivocal results in screening tests. In comparison with macroprolactin, little is known about big PRL. It is a more consistent component of total serum PRL but rarely, if ever, the cause of hyperprolactinaemia. Further research is required into the nature of macroprolactin and big PRL, the relationships between high molecular mass forms of PRL, and their clinical significance.

Prolactin and macroprolactin: a case report of hyperprolactinaemia highlighting the interpretation of discrepant results.

Immunoassay methods for prolactin detect macroprolactin (i.e. high molecular mass complexes of prolactin) to various degrees. Therefore it is generally assumed that the widely differing results by methods that measure both moieties to a differing extent are due to the presence of macroprolactin. We present a case which challenges such an assumption and suggest that precipitation by polyethylene glycol is the most reliable screen for identifying macroprolactin (and/or interfering antibodies if present).

Concomitant occurrence of macroprolactin, exercise-induced amenorrhea, and a pituitary lesion: a diagnostic pitfall. Case report.

The authors report the case of a 37-year-old woman who presented with amenorrhea and an increased level of serum prolactin. Magnetic resonance images of the pituitary revealed a lesion with characteristics consistent with those of a microadenoma. Transsphenoidal exploration was performed, but a prolactinoma was not found. After endocrinological review, the patient's hyperprolactinemia was found to be caused by the presence of macroprolactin and her amenorrhea was due to intense exercise and low body weight. Macroprolactin is an isoform of prolactin that is variably reactive in assays for prolactin, but displays minimum bioactivity in vivo. Patients with macroprolactin are mostly asymptomatic. This phenomenon may cause elevated prolactin values, which the authors view as apparent hyperprolactinemia. The presence of macroprolactin is an underrecognized problem, occurring in as many as 15 to 20% of patients with elevated prolactin values and often leading to unnecessary, expensive diagnostic procedures and inappropriate treatment. The presence of macroprolactin should always be suspected when the patient's clinical history or clinical or radiological data are incompatible with the prolactin value. Physicians dealing with diagnosis and treatment of hyperprolactinemia (general practitioners, gynecologists, neurosurgeons, endocrinologists, and biochemists) should be aware of the potentially misleading nature of macroprolactin.

Macroprolactinaemia: contribution to hyperprolactinaemia in a district general hospital and evaluation of a screening test based on precipitation with polyethylene glycol.

For a period of 12 months all samples submitted for serum prolactin (PRL) assay and with PRL > 700 mU/L were examined by gel filtration chromatography. In 17 (25%) of 69 samples we found macroprolactin. The Delfia and Immuno 1 immunoassay systems gave similar PRL results with samples containing macroprolactin whereas the ACS 180 system gave lower results. With the Delfia and Immuno 1 systems samples containing substantial quantities of macroprolactin showed low recovery of PRL after precipitation with polyethylene glycol 6000 (PEG 6000) and this technique can be used as a screening test for macroprolactinaemia. We conclude that macroprolactinaemia is a common phenomenon and, in assays which detect this species, is a common cause of hyperprolactinaemia. Macroprolactinaemia may contribute to the difficulty in establishing an upper limit of the reference range for serum PRL. In our experience, patients with macroprolactinaemia do not exhibit features of the hyperprolactinaemia syndrome and it is important to recognize macroprolactin as the cause of hyperprolactinaemia to avoid unnecessary investigation and treatment.

Hypercalcaemia due to calcium binding IgM paraprotein in Waldenström's macroglobulinaemia.

A case of Waldenström's macroglobulinaemia with asymptomatic hypercalcaemia is reported in which calcium binding to the paraprotein was found. This is the first report of this phenomenon in Waldenström's macroglobulinaemia and the first report of calcium binding to an IgM paraprotein.