A Case of macro-TSH masquerading as subclinical hypothyroidism

Abstract

A 47-year-old man was commenced on levothyroxine following a diagnosis of subclinical hypothyroidism with nonspecific symptoms. Despite increasing doses of levothyroxine, his thyroid-stimulating hormone (TSH) remained elevated and he was referred for further assessment as he was unable to tolerate further titration. On assessment, his thyroid function demonstrated an elevated TSH and elevated free-T4. The initial impression was of iatrogenic thyrotoxicosis, with possible underlying thyroid hormone resistance, TSHoma or assay interference. After discontinuation of levothyroxine, free-T4 normalised but TSH remained elevated. There was a normal response to thyrotropin-releasing hormone (TRH) testing. T3 suppression testing demonstrated free-T4 reduction but persistently high TSH. THRβ sequencing was normal. TSH measurement by alternative assays revealed discrepant results. Gel filtration chromatography revealed the presence of high-molecular weight TSH variant alongside normal TSH. Macro-TSH is a rare phenomenon with spuriously elevated TSH and which may mimic subclinical hypothyroidism. Recognition of macro-TSH avoids misdiagnosis and prevents inappropriate treatment.

Background

Macro-thyroid-stimulating hormone (TSH) is seemingly a relatively rare phenomenon but potentially under-recognised. It remains an important differential in the assessment of patients with thyroid function tests that are incogruent with the clinical picture.

When recognised, a diagnosis of macro-TSH may provide reassurance to patients and clinicians. Importantly, it may prevent inappropriate treatment.

Case presentation

A 47-year-old man presented to his General Practitioner reporting of fatigue and weight gain. The initial workup included thyroid function tests, which revealed a normal free-T4 of 14.3 pmol/L (normal range 12–22) and an elevated TSH of 28.4 mIU/L (normal range 0.27–4.2). Anti-thyroid-peroxidase antibody titre was normal. A diagnosis of subclinical hypothyroidism was made and he was commenced on levothyroxine 50 μg/day. Over the following 12 months, his levothyroxine was uptitrated on the basis of continued TSH elevation. At a dose of 150 μg/day, the patient developed sweating, insomnia, palpitations and heat intolerance. He was unable to tolerate this dose and was subsequently referred to his local endocrinology service for assessment.

At the time of assessment, the previous history included ongoing investigations for frequent ventricular ectopics and a possible diagnosis of arrhythmogenic right ventricular cardiomyopathy. He was prescribed bisoprolol 2.5 mg/day but took no other medications or supplements.

Both parents were deceased, and he had one sister and one son. There was no documented family history of dysthyroidism nor of structural thyroid disease. He was a nonsmoker.

On initial examination, he was broadly euthyroid with no goitre, no signs of thyroid eye disease and regular pulse of 60 bpm. The visual fields were full to confrontation.

At this visit, his thyroid function tests revealed an elevated free-T4 (26.9 pmol/L) and elevated TSH (11.67 mIU/L). It was felt that the diagnosis was one of iatrogenic thyrotoxicosis with potential underlying TSHoma, thyroid hormone resistance or of assay interference.

Levothyroxine was discontinued and the patient reassessed after 6 weeks. Following discontinuation TSH remained elevated (20.26 mIU/L), but free-T4 normalised (13.2 pmol/L). The patient’s symptoms had resolved.

Investigations

THR-beta sequencing was normal, making a diagnosis of thyroid hormone resistance highly unlikely. Dynamic testing was undertaken to elucidate the underlying diagnosis. TRH stimulation testing was performed and the results are shown in table 1. A prompt response to TRH was seen, which might be seen in thyroid hormone resistance but would render a diagnosis of TSHoma unlikely. A T3 suppression test (80 μg/day for 8 days) was performed and the results are shown in table 2. It can be seen that after 8 days of T3 exposure, there is an appropriate fall in free-T4 but a persistently elevated TSH. Although such a response might be seen with TSHoma, most cases of thyroid hormone resistance would be expected to demonstrate a suppression response in TSH.

Table 1.

Response to TRH stimulation testing

Time (min)	0	20	60
TSH mIU/L	20.26	48.16	43.43

TSH, thyroid-stimulating hormone.

Table 2.

T3 stimulation testing (80 mcg/day for 8 days)

	Day 0	Day 8
Free T4 pmol/L	13.4	8.6
TSH mIU/L	20.04	12.08
Free T3 pmol/L	6.5	–

TSH, thyroid-stimulating hormone.

Thyroid function tests were performed on different platforms (Roche Cobas and Abbott Architect) and returned discrepant results for TSH as shown in table 3. polyethylene-glycol (PEG) precipitation was performed locally following which TSH fell from 12.9 mIU/L at baseline to 2.0 mIU/L post-PEG, representing a recovery of 15.5%.

Table 3.

Analysis of patients serum on alternative assay platforms

	Roche Cobas	Abbott Architect
FT4 pmol/L	16.1	14.0
TSH mIU/L	12.21	1.7

TSH, thyroid-stimulating hormone.

Differential diagnosis

In the absence of levothyroxine, the patient appeared clinically euthyroid. The symptoms reported in this case, fatigue and weight gain, are commonly encountered in subclinical hypothyroidism but are nonspecific. As such, it is difficult to distinguish subclinical hypothyroidism from normal underlying thyroid function on clinical examination alone. The dynamic testing performed would not be clearly in keeping with either TSHoma or with thyroid hormone resistance. There was, however, in short, a constancy of TSH elevation in the face of varying levels of free T4. This may be seen with underlying assay interference as suggested in the discrepancy between the Roche and Abbott platforms. A low recovery of TSH following PEG precipitation would suggest the presence of a high-molecular weight substance as a source of interference.

Gel filtration chromatography was performed under the direction of Prof Samuel Refetoff at the University of Chicago to confirm the underlying diagnosis. As shown in figure 1. The patient’s serum is represented in orange, control TSH in green and a high-molecular weight IgG marker in blue. Under basic conditions, the patient’s serum is eluted in two fractions, one corresponding to control TSH and the other with high molecular weight. After acidification, it can be seen that some of this high-molecular weight fractions are displaced towards the peak of control TSH. This is indicative of partial dissociation of TSH from IgG following acidification and overall is in keeping with a diagnosis of macro-TSH.

Figure 1.

Gel filtration chromatography of patient’s serum demonstrating a high molecular weight variant of TSH, which dissociates on acidification in keeping with IgG bound macro-TSH. TSH, thyroid-stimulating hormone. PBS: Phosphate-buffered saline. MW: molecular weight

Treatment

Following a diagnosis of macro-TSH, the patient was reassured and all treatments were discontinued.

Outcome and follow-up

At 12 months following the discontinuation of levothyroxine, the patient remained well to follow-up and free of dysthyroid symptoms.

Discussion

Subclinical hypothyroidism, as represented by elevated TSH and normal free T4, is a common phenomenon that may reach a prevalence as high as 10% in certain populations.¹ Guidelines advocate treatment of subclinical hypothyroidism where the patient is symptomatic or where the TSH exceeds 10 mIU/L.¹

Interference in thyroid function immunoassays presents a potential confounder to the interpretation of thyroid function tests and should be considered particularly where the test result does not align with the clinical picture.²

Macro-TSH is a high-molecular weight variant of TSH, which is IgG bound and is not biologically active.³ It presents with spuriously elevated TSH, which often mimics subclinical hypothyroidism. Very high levels of TSH without a concomitant fall in free T4 might raise the suspicion of macro-TSH, but no specific thresholds of TSH have been identified that would distinguish macro-TSH from subclinical hypothyroidism on the basis of TSH alone. It is a relatively rare phenomenon, with an estimated prevalence of <1% among those presenting with biochemical subclinical hypothyroidism when stringent testing is applied.⁴ All commercially available immunoassays for TSH are susceptible to interference from macro-TSH to a greater or lesser extent.⁴ The Abbott Architect platform is the least susceptible and would explain the lower TSH result seen on this platform with this patient.

The development of thyrotoxic symptoms following the introduction of levothyroxine in this patient was considered a useful indicator that there was clinical discordance, and a similar response was reported in another confirmed case.⁵

Depending on the level of macro-TSH, however, elevated concentrations may be seen across multiple platforms. While gel filtration chromatography is not widely available in clinical laboratories, the application of PEG precipitation provides a useful discriminator of potential macro-TSH. Although there is a paucity of evidence in defining a useful threshold, recovery rates of <20% have been proposed as suggestive of macro-TSH⁶ and <10% as being strongly suggestive.⁴

Confirmation of the presence of macro-TSH is by gel filtration chromatography. PEG precipitation, as described, is much more widely available across laboratories and should suffice in most cases for making a diagnosis of macro-TSH. Making such a diagnosis provides reassurance to both patients and clinicians. More importantly, by excluding subclinical hypothyroidism, it avoids unnecessary treatments with thyroid hormone replacement and its attendant risks. Such sources of interference are an important consideration where there is clinical incongruence or where symptoms are vague or nonspecific.

Learning points.

• Macro-thyroid-stimulating hormone (TSH) is a rare source of interference in thyroid function tests and is not, of itself, indicative of any underlying thyroid dysfunction.

• Nonspecific symptoms should not automatically be ascribed to thyroid dysfunction.

• Diagnosis of macro-TSH avoids unnecessary treatments with thyroid hormone replacement.

Ethics statements

Patient consent for publication

Obtained.