Extremely Low Doses of Heparin Release Lipase Activity into the Plasma and Can Thereby Cause Artifactual Elevations in the Serum-Free Thyroxine Concentration as Measured by Equilibrium Dialysis

Abstract

Heparin can cause an artifactual elevation in the concentration of unbound (free) thyroxine (T4) in the plasma, particularly when measured by equilibrium dialysis. The lipase released into the plasma by heparin acts on substrate (triglycerides; TG) in the plasma in vitro to release nonesterified (free) fatty acids (FFA), which, in high concentrations, inhibit the binding of T4 to its plasma binding proteins. This artifact occurs only in the presence of sufficient substrate (serum TG greater than approximately 180 mg/dL), and is most pronounced in methods requiring long incubation times. We observed this artifact in a patient receiving intralipid and subcutaneous (sc) heparin. Plasma-free T4, when measured by equilibrium dialysis, was elevated, but was normalized when the in vitro generation of FFA during equilibrium dialysis was prevented by prior treatment of the sample with protamine to inhibit lipoprotein lipase and with an antibody to hepatic triglyceride lipase. This observation caused us to investigate formally whether heparin, at standard sc doses or at iv doses even lower than those that are commonly used to flush iv lines (100-300 U), could also cause this artifact. We gave increasing doses of heparin at weekly intervals to each of three normal volunteers and measured FFA generation in their plasma (supplemented with 250 mg/dL triglycerides) under conditions simulating equilibrium dialysis. We found that, indeed, iv doses of heparin as low as 0.08 U/kg (5.6 U in a 70-kg subject) as well as a standard dose of sc heparin (5000 U) could release significant lipase activity into the plasma and, in the setting of sufficient substrate, cause enough in vitro generation of FFA to artifactually increase the serum-free T4 concentration when measured by equilibrium dialysis. These results indicate that equilibrium dialysis may not always be the best method for assessing serum-free T4 concentrations in hospitalized patients, and should be taken into account when interpreting previous studies demonstrating inhibitors of T4-serum protein binding in sera from hospitalized patients.

A Study of Thyroid Profile and Sick Euthyroid State in Patients with Acute Coronary Syndrome

“…TSH value remain same in both worst outcome group and improved group in our study where the study by Tauber JL et al reported that in very sick condition T4 is low but the TSH remain normal. 15 There is an association between high rT3 value and worst outcome in our study where report by Utiger RD et al reveals that the rT3 is well associated with high mortality 16 .…”

The role of cytokines and cortisol in the non-thyroidal illness syndrome following acute myocardial infarction

“…This is also demonstrated by the fact that in only four patients serum T 3 decreased below the normal range values and in none of them did FT 4 , T 4 or FT 4 I fall to subnormal levels. It could be suggested that because of heparin treatment, FT 4 was apparently higher in our patients than it would be without this treatment, particularly when free T 4 was measured by equilibrium dialysis (17). For this reason free T 4 was also estimated by a second method (ELISA) and the changes were similar.…”

The impact of low triiodothyronine levels on mortality is mediated by malnutrition and cardiac dysfunction in incident hemodialysis patients

“…In incident dialysis patients, however, only T 3 , but not fT 3 , levels were associated with worse all-cause and CV mortality after adjustment for confounding factors (31). This may be attributed to a lower technical specificity of fT 3 measurement by RIA (20), especially for the stored samples (21), and a smaller influence of heparin on T 3 than on fT 3 (22,33). In addition, T 3 levels are determined as a total form rather than as a free form in most hospitals in Korea due to the financial benefits and convenience.…”