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.

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.

Macroprolactin(s): composition and reactivity in immunoassays and laboratory interpretation of results of an unusual patient serum.

BACKGROUND: Macroprolactin is a high molecular mass complex of prolactin that may be the cause of elevated serum prolactin as determined by immunoassay. The composition of macroprolactin and its reactivity in immunoassays are variable but the complex has minimal bioactivity in vivo. Hyperprolactinaemia due to unrecognized macroprolactinaemia can lead to misdiagnosis and mistreatment. METHODS: Serum from a patient with an unusual pattern of immunoreactivity was distributed to three users of each of the most popular immunoassays represented in the UK National External Quality Assessment Scheme (NEQAS) for prolactin. Clinical details were provided and participating centres were invited to investigate the prolactin content of the specimen according to their local protocol, and to comment on their results. The nature of the macroprolactin in the specimen was investigated in detail by gel filtration chromatography of the native serum and of the serum after adsorption of IgG with protein A, and by affinity chromatography with concanavalin A. RESULTS: Gel filtration studies revealed two peaks of macroprolactin in this serum. These macroprolactins were shown to be different in their IgG content and degree of glycosylation. All eight immunoassays reacted strongly with the macroprolactin present. The majority (78%) of centres that interpreted their results either demonstrated the presence of macroprolactin in the specimen, or suggested it as a likely cause of the hyperprolactinaemia. However, two centres inappropriately excluded macroprolactinaemia as the cause of the elevated prolactin, and a further two did not consider it at all. Data from previous UK NEQAS distributions (between 1996 and 2003) of macroprolactin containing sera are presented which suggest that the frequency of recognition of macroprolactin as a possible cause of hyperprolactinaemia has increased over time. CONCLUSIONS: Very high molecular mass forms of prolactin and the presence of multiple molecular mass forms, as detected in the case presented here, are uncommon. Also, the pattern of immunoreactivity reported in this specimen was unusual as most macroprolactins studied previously react less strongly in, for example, the Bayer ADVIA Centaur assay compared to the Roche E170 assay. Both peaks of macroprolactin in this serum reacted in all assays tested. This case highlights the variable nature and immunoreactive behaviour of macroprolactin species.

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.

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.

HDL cholesterol and the acute phase reaction following myocardial infarction and acute pancreatitis.

The response of HDL in the acute phase reaction following myocardial infarction (MI) (82 subjects) and acute pancreatitis (AP) (30 subjects) has been examined and compared with that in a control group (76 subjects) admitted to hospital with suspected MI but in whom the diagnosis was not subsequently confirmed. The temporal and quantitative characteristics of the changes in concentration of the positive acute phase reactants fibrinogen and alpha 1-antitrypsin and the negative acute phase reactants albumin and LDL were similar in the myocardial infarction and acute pancreatitis subjects. In contrast, the response of HDL was different to that of the other transport proteins both within each experimental group and between the two groups. This indicated that the response of HDL cannot be regarded as simply part of a secondary negative acute phase reaction. After adjustment for changes in plasma volume, the data indicated that hepatobiliary dysfunction was probably a major factor in the negative response of HDL following acute pancreatitis and may have contributed to its response following myocardial infarction.

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.

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).

Intra-operative parathyroid hormone assay for simplified localization of parathyroid adenomas.

Lack of success in parathyroid surgery is usually due to failure to identify the abnormal parathyroid gland correctly at operation. The surgeon may be helped by rapid parathyroid hormone (PTH) assay in peripheral blood after removal of a suspected adenoma, and by frozen section histology, but these are not true localization techniques. We have adapted a non-isotopic immunoassay for rapid measurement of PTH in samples from the upper, middle and lower thyroid veins taken at operation, before exploration begins. Fifteen patients with primary hyperparathyroidism were operated on. In 10 the parathyroid adenoma was located easily, and was associated with high local venous PTH levels. In four patients the abnormal parathyroid was not immediately apparent but the assay indicated its location, which was confirmed after further exploration. In one patient there was no difference in PTH levels in the six venous samples. An ectopic adenomatous gland was successfully identified behind the thymus. The operation was successful in all patients as shown by a fall in the plasma calcium to the normal range. We conclude that intra-operative selective venous sampling and rapid PTH assay facilitates operative localization of parathyroid adenomas.

Failure of the short ACTH test to unequivocally diagnose long-standing symptomatic secondary hypoadrenalism.

Recent guidelines propose that secondary hypoadrenalism can be reliably diagnosed, in the absence of acute ACTH deficiency or glucocorticoid use, by means of the short ACTH test (Synacthen). We report a patient who maintained a normal response to exogenous ACTH stimulation despite symptomatic chronic ACTH deficiency proven by the insulin tolerance and overnight metyrapone tests. It is suggested that partial ACTH deficiency may prevent involution of the adrenal cortex and preserve the cortisol response to ACTH stimulation. A normal cortisol response in the short ACTH test does not therefore exclude the possibility of clinically relevant ACTH deficiency.