Q J Med 2001; 94: 471-473
© 2001 Association of Physicians
Abnormal serum free thyroid hormone levels due to heparin administration
From the Departments of Medicine, and 1 Clinical Biochemistry, University Hospital of Wales, Cardiff, UK
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Summary |
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Fractionated or unfractionated heparin may produce artefactual elevation in measured concentrations of free thyroid hormones. Although the specific cause is unknown, it may be a consequence of displacement of thyroid hormones from their binding sites by free fatty acids liberated in vitro. We describe four cases of heparin-induced abnormalities in free thyroid hormone measurements where some diagnostic confusion was generated. Increasing physician awareness of this poorly appreciated entity may avert diagnostic confusion and unnecessary investigation.
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Introduction |
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We describe changes in serum free thyroxine (fT4) and free tri-iodothyronine (fT3) with normal levels of TSH during heparin treatment. fT4 and fT3 concentrations may rise markedly after both fractionated and unfractionated heparin, independently of the route of administration.1,2 However, the changes are an artefact, related to displacement of thyroid hormones from their binding sites. This phenomenon is often poorly appreciated by clinicians, and may cause diagnostic confusion, prompting unnecessary investigation. We present four cases that illustrate the effects of heparin on thyroid function tests, along with a review of the related literature.
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Case reports |
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Patient 1
A 62-year-old lady was admitted with poor mobility, progressive lower limb weakness and quadriceps pain. She had an asymmetrical weakness of both legs with prominent quadriceps wasting and minimal distal sensory loss. She was commenced on 3400 units of subcutaneous tinzaparin daily as prophylaxis against venous thrombo-embolism.
She was eventually diagnosed with diabetic amyotrophy, but thyroid function tests were performed 48 h after admission as part of the investigation of the proximal myopathy. These revealed a raised fT4 and fT3 with a normal TSH (Table 1
). This was confirmed on a repeat sample. Prior to referral to the endocrine unit, the thyroid abnormalities were investigated with negative thyroid auto-antibodies and an I123 isotope scan of the thyroid that showed normal uptake. Serum albumin was measured and protein electrophoresis performed; both were normal. Serum cholesterol was 7.2 mmol/l and triglycerides 2.1 mmol/l.
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Patient 2
A 42-year-old lady was admitted with pleuritic chest pain. There was a history of pulmonary embolism 1 year previously, for which she had received 6 months of anticoagulation with warfarin. A recurrent pulmonary thrombo-embolic episode was suspected, and she was commenced on heparin, starting with 5000 units intravenously.
Thyroid function tests were performed 12 h after admission as investigation of a raised mean cell volume on full blood count. These showed raised fT4 and fT3 with a TSH concentration within the normal range (Table 1
). After discontinuation of heparin, the patient received warfarin, and this was associated with normalization of the thyroid function tests (fT4 16.0 pmol/l and TSH 1.72 mU/l).
Patient 3
A 40-year-old male was admitted with acute onset of dyspnoea, chest pain and atrial fibrillation. Four months previously he had been diagnosed with an anaplastic astrocytoma, and had undergone neurosurgical debulking, chemotherapy and radiotherapy. His post-operative period was complicated by deep-vein thrombosis. In view of this, pulmonary thrombo-embolic disease was suspected, and he was commenced on subcutaneous tinzaparin 20 000 units daily. Despite treatment, he suffered a massive pulmonary embolism and died 72 h later. After receiving heparin, thyroid function tests were performed for investigation of atrial fibrillation, which once again demonstrated raised fT4 and fT3 with normal TSH concentrations (Table 1).
Patient 4
A 41-year-old female was admitted to hospital with a sudden onset of pleuritic chest pain and atrial fibrillation. There was no significant previous medical history. Pulmonary embolism was suspected as she had recently returned on a long-haul flight. She was commenced on intravenous heparin. Thyroid function tests performed 48 h later showed raised fT4 and fT3 with normal TSH concentrations (Table 1).
Overall results
Thyroid function tests repeated after discontinuation of heparin were normal in three of the above cases (not repeated in one case). In two cases, the initial samples were re-analysed elsewhere using Delfia assay to exclude an interfering antibody. Free T4 and free T3 obtained with this were considerably higher than those with the Bayer ACS-180 Assay used for all the above analyses.
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Discussion |
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Thyroid function tests are frequently performed in hospitalized patients, and abnormalities are common.3 Elevated free thyroid hormones with normal TSH levels are most often due to drugs or interference from heterophile antibodies in the serum,4 but occasionally, this profile may be seen in association with a TSH-secreting pituitary tumour. Many drugs can interfere with the measurement of thyroid function tests and pose diagnostic uncertainties.5 In particular, heparin, a drug with expanding clinical roles in primary and secondary care, is recognized to have confounding effects on thyroid function tests. However, these effects are not well appreciated by clinicians, possibly because there is no reference to this phenomenon in standard pharmacological texts.6,7 Lack of awareness of this effect prompted inappropriate investigations such as a thyroid uptake scan, measurement of thyroid antibodies and repeated measurement with different assays in some of our cases.
Abnormalities in thyroid function tests may occur with either fractionated or unfractionated heparin. The mechanism underlying these abnormalities is not fully understood, but displacement of thyroid hormones from their binding sites by heparin-induced rises in free fatty acid (FFA) has been implicated. Heparin produces a release of lipoprotein lipase from the vascular endothelium, producing a rise in the levels of free fatty acid (FFA). A measurable increase in FFA concentration is usually demonstrable within 15 min of administration of heparin intravenously, even with very low doses, but requires the presence of adequate amounts of the substrate (triglyceride levels >180 mg/dl). High levels of FFA inhibit the binding of thyroid hormones to their plasma binding proteins, producing a rise in measured quantities of thyroid hormones. Since serum albumin has higher-affinity FFA binding sites, its concentration has an important effect on FFA-induced displacement of thyroid hormones. Typically, fT4 concentrations are unaffected when the FFA:albumin molar ratio is <5:1.8 Such factors might explain why abnormalities of thyroid function tests are not seen in all patients treated with heparin. Similarly, mild elevations of FFA are reported in seriously ill patients, although the rises may be insufficient to account for non-thyroidal abnormalities in thyroid function tests in these patients.8
Since the release of FFA and displacement of thyroid hormones continues in vitro, pre-analytical delay can confound further measurements of thyroid function.9 In all four patients, there was a delay of between 2 and 5 days before samples were analysed, so allowing the in vitro displacement of FT4 and FT3 to occur. Similarly, there were larger discrepancies associated with the delay in processing samples by the Delfia assay (Table 1).
There is evidence that in samples collected 10 h or more after an unfractionated heparin injection, interference is minimal.1 However, low-molecular-weight heparins have greater bioavailability and longer half-lives, making such generalizations less accurate. One study demonstrated virtually normal fT4 levels when samples were collected 24 h after the last injection.1 Similarly, the induced abnormalities of thyroid hormone measurements do not appear to be dose-related. Intravenous doses as low as 0.08 U/kg, as well as standard doses of subcutaneous heparin could release significant lipase activity into serum.2
The roles for heparin therapy in clinical practice are expanding but, as the above cases illustrate, heparin is capable of inducing artefactual abnormalities in thyroid function tests. Consequently, greater awareness by clinicians to the association between abnormalities of thyroid function tests and heparin is required if diagnostic confusion, with inappropriate investigation and treatment, is to be avoided. Ideally, when thyroid dysfunction is suspected, samples should be collected prior to administration of heparin and, if a sample is collected while the patient is on heparin, this fact should be clearly stated on the request form.
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Notes |
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Address correspondence to Dr K. Laji, Diabetes Unit, Royal Glamorgan Hospital, Llantrisant, South Wales CF72 8XR. e-mail: laji{at}doctors.org.uk
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References |
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1. Stevenson HP, Archbold GP, Johnston P, Young IS, Sheridan B. Misleading serum free thyroxine results during low molecular weight heparin treatment. Clin Chem1998; 44:1002–7.
2. Jaume JC, Mendel CM, Frost PH, Greenspan FS, Laughton CW. 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. Thyroid1996; 6:79–83.[Web of Science][Medline]
3. Toubert ME, Chevret S, Cassinat B, Schlageter MH, Beressi JP, Rain JD. From guidelines to hospital practice: reducing inappropriate ordering of thyroid hormone and antibody tests. Eur J Endocrinol2000; 142:605–10.[Abstract]
4. Ward G, McKinnon L, Badrick T, Hickman PE. Heterophilic antibodies remain a problem for the immunoassay laboratory. Am J Clin Pathol1997; 108:417–21.[Web of Science][Medline]
5. Wenzel KW. Disturbances of thyroid function tests by drugs. Acta Med Austriaca1996; 23:57–60.[Web of Science][Medline]
6. British National Formulary, vol. 40. British Medical Association and the Royal Pharmaceutical Society of Great Britain, 2000.
7. Monthly Index of Medical Specialties. London, 12, Haymarket Medical Ltd, 2000.
8.
Mendel CM, Frost PH, Cavalieri RR. Effect of free fatty acids on the concentration of free thyroxine in human serum: the role of albumin. J Clin Endocrinol Metab1986; 63:1394–9.
9.
Mendel CM, Frost PH, Kunitake ST, Cavalieri RR. Mechanism of the heparin-induced increase in the concentration of free thyroxine in plasma. J Clin Endocrinol Metab1987; 65:1259–64.
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