Total and free serum concentrations of thyroxine and triiodothyronine were measured in 122 subjects with hypothyroidism who were clinically well while receiving conventional replacement treatment with thyroxine. In a third of patients concentrations of total and free thyroxine were raised, often considerably; nevertheless concentrations of total and free triiodothyronine were usually normal. Though significant correlations were obtained between total triiodothyronine concentrations and total thyroxine concentrations (p <0 001) and between the triiodothyronine concentrations and free thyroxine concentrations (p<0001) the slope of the line of the regression equation describing these correlations was small, hence large increases in both total and free thyroxine concentrations were accompanied by only modest increases in total and free triiodothyronine concentrations.The presence of total or free thyroxine concentrations above normal in patients taking thyroxine therefore are not necessarily ofclinical consequence. In the assessment of adequacy of replacement treatment with thyroxine the most logical combination of in vitro thyroid function test results may be a normal thyrotrophin concentration and normal free triiodothyronine concentration.
Serum thyroxine was consistently unmeasurable by radioimmunoassay in an elderly patient with myxoedema after successful treatment with oral thyroxine. Abnormal binding of thyroxine was suspected and shown to be due to the presence in serum of antibodies of the IgG variety. The characteristics of these antibodies with respect to their binding of thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and human thyroglobulin (Tg) were systematically studied. Three preparations of Tg, and t4, T3 and rT3 were examined for their ability to compete with 125I-Tg, 125I-T4, 125I-T3 and 125I-rT3 for binding to the antibodies. For each tracer used the order of competitive efficiency was Tg greater than T4 greater than T3 greater than rT3. This provides for the first time direct evidence that iodothyronine reacting antibodies occurring in man are generated against Tg. All three iodothyronines were able to inhibit tracer binding of labelled iodothyronines completely, the order of effectiveness being T4 greater than T3 greater than rT3, suggesting antibodies with one type of binding site and that these were probably raised against a Tg sequence incorporating T4, although there was some evidence for the existence of a minor subpopulation of antibodies with higher specificity for T3. Complete displacement of labelled Tg by cold iodothyronines, however, was not possible. The experimental evidence suggests two classes of Tg antibodies, 70% of which were directed towards the T4 containing region, and 30% directed against other part(s) of the Tg molecule. Despite the presence of such Tg antibodies conventional haemagglutination tests of the patient's serum for Tg antibodies were negative.
Free thyroid hormone concentrations measured by Amerlex assays were studied in subjects with inherited disorders of thyroxine-binding globulin (TBG) synthesis, variant albumins with a high avidity for T4, and iodothyronine-binding autoantibodies. Free T4 (fT4) and free T3 (fT3) levels were normal in euthyroid subjects with TBG deficiency and excess. Free T3 concentration was in the low normal range in subjects having a variant albumin but fT4 (Amerlex) was erroneously elevated because of the enhanced affinity of the 125I-T4 analogue employed in the assay for the abnormal albumin. The 125I-T3 analogue used in the fT3 assay does not bind more strongly to this variant albumin than to normal albumin. Amerlex assays for fT4 and fT3 in patients with iodothyronine-binding autoantibodies to thyroglobulin give variable results according to the specificity of the autoantibodies: non-specific antibodies cause extraordinarily high values even in hypothyroid patients; fT3 measurements may be appropriate in patients with T4-specific antibodies and even in some with T3-specific antibodies. The presence of such antibodies should be suspected if the results of Amerlex assays for fT4 and fT3 are discordant or are inconsistent with the clinical picture or TSH levels.
Three patients who were treated with ketorolac tromethamine (Toradol), an injectable nonsteroidal anti-inflammatory drug for pain management, developed acute renal failure or hyperkalemia or both. These complications were reversible in two cases after discontinuing the drug. Clinical conditions preexisted in each patient that rendered them susceptible to the renal complications of nonsteroidal anti-inflammatory use. It is well known that caution should be observed while using nonsteroidal anti-inflammatory drugs in patients whose renal function may be preserved through prostaglandin-mediated vasodilatory effects. The same cautions apply to ketorolac. Since its major marketed use is as an analgesic and its potent effect on prostaglandin synthesis may not be well recognized, those cautions must be emphasized.
SUMMARY.Total serum calcium concentration was raised in a 63-year-old lady with multiple myeloma and markedly elevated serum IgA x-paraprotein concentration. Symptoms of hypercalcaemia were absent, and serum ionized calcium was normal, suggesting calcium binding by the abnormal protein. This was demonstrated directly after isolation of the paraprotein and characterization of the calcium/protein interaction. After reduction of the paraprotein with mercaptoethanol, sodium dodecyl sulphate polyacrylamide gradient gel electrophoresis revealed two bands corresponding to light and heavy chains, but under non-reducing conditions the isolated paraprotein migrated in a series of bands, possibly representing polymeric forms of the basic immunoglobulin moiety. Additional key phrases: ionized calcium; polyacrylamide gradient gel electrophoresis; mercaptoethanol reductionApproximately half the total serum calcium is bound by albumin, with a small proportion complexed by various anionic species. The concentration of free or ionized calcium in the plasma is thought to be the physiologically relevant moiety,' as bound calcium is not immediately available to the tissues. There have been occasional reports of abnormal calcium binding by paraproteins (both IgGs) from patients with m y e l o m a t~s i s ,~-~ in whom total serum calcium was raised, while ionized calcium concentration was normal. Binding of calcium by the myeloma proteins was demonstrated in both cases, and the importance of measuring ionized calcium concentration in patients with myeloma presenting with hypercalcaemia was stressed, in order to avoid vigorous and potentially hazardous treatment for hypercalcaemia.A similar case will be described in whom total serum calcium was raised while the ionized fraction was normal. Isolation of the paraprotein (in this case an IgA) was performed using a combination of affinity chromatography and high performance ion exchange liquid chromatography, and the calcium binding characteristics of the purified IgA examined using equilibrium Correspondence: Dr C J Pearce.dialysis. Further characterization of the paraprotein on polyacrylamide gradient gel electrophoresis (PAGGE) revealed a complex pattern of multiple bands of high molecular weight species, probably representing polymers of the basic 180 kDa immunoglobulin moiety. CASE REPORTMrs S H, a 67-year-old widow, was referred by her general practitioner with a 6 week history of increasingly severe generalized back pain. Radiology of the thoracic and lumbar spine revealed multiple vertebral collapse, and a bone marrow examination showed an excess of plasma cells. Serum albumin concentration was 35 g/L, globulins 73 g/L, and the total serum calcium concentration was 3.5 mmol/L, measured on a SMAC-2 autoanalyser using conventional methodology. Serum immunoelectrophoresis revealed an IgA x-paraprotein. Despite direct questioning there were no symptoms of hypercalcaemia, the Q-T interval on electrocardiography was not shortened, and the serum ionized calcium concentration was within t...
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